SGLT-2 inhibitors for treating metabolic disorders in patients with renal impairment or chronic kidney disease

ABSTRACT

The present invention relates to certain SGLT-2 inhibitors, such as ertugliflozin or a co-crystal or a pharmaceutically acceptable salt thereof, for treating and/or preventing metabolic disorders, such as type 1 or type 2 diabetes mellitus or pre-diabetes, in patients with renal impairment or chronic kidney disease (CKD). The present invention also relates to methods for preventing neuronal damage following the incidence of ischemic stroke and close-head traumatic brain injury in animals comprising the step of administering to an animal, in need of such treatment, a therapeutically effective amount of ertugliflozin or a co-crystal or a pharmaceutically acceptable salt thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase application under 35 U.S.C. §371 of PCT Application No. PCT/US15/059122, filed Nov. 5, 2015, whichpublished as W02016/077126 A1 on May 19, 2016, and claims priority under35 U.S.C. § 365(b) from U.S. provisional patent application No.62/139,211, filed Mar. 27, 2015 and U.S. provisional patent applicationNo. 62/077,555, filed Nov. 10, 2014.

FIELD OF THE INVENTION

The present invention relates to certain SGLT-2 inhibitors, such asertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof, for treating and/or preventing metabolic disorders, such astype 2 or type 1 diabetes mellitus or pre-diabetes, in patients withrenal impairment or chronic kidney disease (CDK).

BACKGROUND

Recently, sodium-glucose co-transport (SGLT) inhibitors have been foundto be effective in treating prediabetes, type 1 or type 2 diabetesmellitus. Particularly SGLT2 inhibitors have been shown to block thereabsorption of glucose from the renal filtrate in the glomerulusthereby inducing glucose excretion in the urine. As excess glucose isexcreted, there is a decrease in blood glucose level, decreased hepaticstorage of glucose, decreased insulin secretion and, subsequently,decreased carbohydrate conversion to fat and, ultimately, reducedaccumulated fat. Selective inhibition of SGLT2 is expected to normalizeplasma glucose by enhancing glucose excretion. Consequently, SGLT2inhibitors provide an attractive means for the improvement of diabeticconditions without increasing body weight or the risk of hypoglycemia.See, Isaji, M., Current Opinion Investigational Drugs, 8(4), 285-292(2007). For a general review of SGLT as a therapeutic target, see alsoAsano, T., et al., Drugs of the Future, 29(5), 461-466 (2004).

Nephropathy is a well-established complication of poor glycemic controlin patients with diabetes. An estimated 10-36% of patients with type 2diabetes mellitus (T2DM) have some degree of renal impairment andchronic kidney disease (CKD) is present in approximately 40% of patientswith diabetes. CKD has been classified into 5 stages, where stage 1 iskidney damage with normal GFR (mL/min/1.73 m²) of 90; stage 2 is kidneydamage with a mild decrease in glomerular filtration rate (GFR) (GFR60-89); stage 3 is a moderate decrease in GFR (GFR 30-59); stage 4 is asevere decrease in GFR (GFR 15-29); and stage 5 is kidney failure(GFR<15 or dialysis). The use of a number of anti-diabetes agents isrestricted in patients with renal impairment. Therefore, there is a needfor methods, medicaments and pharmaceutical compositions for thetreatment of metabolic disorders, such as type 2 diabetes, in patientswith renal impairment or chronic kidney disease (CDK).

Additionally, SGLT plays a role at the blood brain barrier in theblood-to-brain transport of glucose during ischemic conditions, andinhibition of SGLT during stroke has the potential to improve strokeoutcomes (Vemula et al., A Functional Role for Sodium-Dependent GlucoseTransport across the Blood-Brain Barrier during Oxygen GlucoseDeprivation, The Journal of Pharmacology and Experimental Therapeutics,Vol. 328:487-495, 2009). Studies have also shown that post-ischemichyperglycemia exacerbates the development of cerebral ischemic neuronaldamage through the cerebral sodium-glucose transporter, and thatneuronal damage following hyperglycemia was not observed followingadministration of phlorizin, an SGLT1 and SGLT2 inhibitor (Yamazaki etal., Post-ischemic hyperglycemia exacerbates the development of cerebralischemic neuronal damage through the cerebral sodium-glucosetransporter, Brain Research 1489:113-120, 2012). Thus, SGLT-2 inhibitorscould be useful for reducing neuronal damage following the incidence ofischemic stroke and close-head traumatic brain injury. Therefore, thereis a need for methods, medicaments and pharmaceutical compositions foruse in the reduction of neuronal damage following the incidence ofischemic stroke and close-head traumatic brain injury.

SUMMARY

The present invention relates to certain SGLT-2 inhibitors for treatingand/or preventing metabolic disorders, such as type 2 diabetes mellitus,in patients with renal impairment or chronic kidney disease (CDK).

Additionally, the present invention relates to certain SGLT-2 inhibitorspreventing neuronal damage following the incidence of ischemic strokeand close-head traumatic brain injury in animals.

In certain embodiments, compounds of Formula (A) and Formula (B) havebeen found to act as sodium-glucose cotransport (SGLT) inhibitors, inparticular, SGLT2 inhibitors and therefore, may be used in the treatmentof diseases mediated by such inhibition (e.g., diseases related toobesity, Type 2 diabetes, and obesity-related and diabetes-relatedco-morbidities) in patients with renal impairment or chronic kidneydisease (CDK). These compounds may be represented by Formulas (A) and(B) as shown below:

wherein R¹ is H, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, Cl, F, cyano,fluoro-substituted (C₁-C₂)alkyl, (C₁-C₄)alkyl-SO₂—, or(C₃-C₆)cycloalkyl; and

R² is (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₂-C₄)alkynyl, 3-oxetanyloxy,3-tetrahydrofuranyloxy, Cl, F, cyano, fluoro-substituted (C₁-C₂)alkyl,(C₁-C₄)alkyl-SO₂—, (C₃-C₆)cycloalkyl, or a (C₅-C₆)heterocycle having 1for 2 heteroatoms each independently selected from N, O, or S.

It is generally understood by those skilled in the art that varioussubstituents may be added to the compounds of Formula (A) or Formula (B)so long as the substituent(s) selected does not adversely affect thepharmacological characteristics of the compound or adversely interferewith the use of the medicament.

Specific compounds of Formula (A) include:(1S,2S,3S,4R,5S)-1-hydroxymethyl-5-[3-(4-methoxy-benzyl)-4-methyl-phenyl]-6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triol;(1S,2S,3S,4R,5S)-5-[3-(4-ethoxy-benzyl)-4-methyl-phenyl]-1-hydroxymethyl-6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triol;(1S,2S,3S,4R,5S)-5-[4-chloro-3-(4-methoxy-benzyl)-phenyl]-1-hydroxymethyl-6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triol;(1S,2S,3S,4R,5S)-5-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-1-hydroxymethyl-6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triol;(1S,2S,3S,4R,5S)-5-[4-fluoro-3-(4-methoxy-benzyl)-phenyl]-1-hydroxymethyl-6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triol;2-(4-methoxybenzyl)-4-((1S,2S,3S,4R,5S)-2,3,4-trihydroxy-1-(hydroxymethyl)-6,8-dioxa-bicyclo[3,2,1]oct-5-yl)benzonitrile;2-(4-ethoxybenzyl)-4-((1S,2S,3S,4R,5S)-2,3,4-trihydroxy-1-(hydroxymethyl)-6,8-dioxa-bicyclo[3,2,1]oct-5-yl)benzonitrile;(1S,2S,3S,4R,5S)-5-[3-(4-ethoxy-benzyl)-4-fluoro-phenyl]-1-hydroxymethyl-6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triol;(1S,2S,3S,4R,5S)-5-{4-fluoro-3-[4-(tetrahydro-furan-3-yloxy)-benzyl]-phenyl}-1-hydroxymethyl-6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triol;(1S,2S,3S,4R,5S)-5-[3-(4-chlorobenzyl)-4-fluorophenyl]-1-hydroxymethyl-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol;(1S,2S,3S,4R,5S)-5-{4-fluoro-3-[4-(oxetan-3-yloxy)-benzyl]-phenyl}-1-hydroxymethyl-6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triol;and(1S,2S,3S,4R,5S)-5-{4-chloro-3-[4-(oxetan-3-yloxy)-benzyl]-phenyl}-1-hydroxymethyl-6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triol.

Specific compounds of Formula (B) include:(1S,2S,3S,4S,5S)-1-hydroxymethyl-5-[3-(4-methoxy-benzyl)-4-methyl-phenyl]-6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triol;(1S,2S,3S,4S,5S)-5-[3-(4-ethoxy-benzyl)-4-methyl-phenyl]-1-hydroxymethyl-6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triol;(1S,2S,3S,4S,5S)-5-[4-chloro-3-(4-methoxy-benzyl)-phenyl]-1-hydroxymethyl-6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triol;(1S,2S,3S,4S,5S)-5-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-1-hydroxymethyl-6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triol;(1S,2S,3S,4S,5S)-5-[4-fluoro-3-(4-methoxy-benzyl)-phenyl]-1-hydroxymethyl-6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triol;(1S,2S,3S,4S,5S)-5-[3-(4-ethoxy-benzyl)-4-fluoro-phenyl]-1-hydroxymethyl-6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triol;and(1S,2S,3S,4S,5S)-5-[3-(4-chlorobenzyl)-4-fluorophenyl]-1-hydroxymethyl-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol.

An SGTL2 inhibitor used in the methods of the present invention is acompound having the formula (4A):

having the chemical name(1S,2S,3S,4R,5S)-5-[4chloro-3-(4-ethoxy-benzyl)-phenyl]-1-hydroxymethyl-6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-trioland described in U.S. Pat. No. 8,080,580. The compound of 4(A) isfurther known as ertugliflozin.

One aspect of the present invention is a method for treating a disease,disorder, or condition modulated by SGLT2 inhibition in animals thatincludes the step of administering to an animal (preferably, a human)with renal impairment or chronic kidney disease (CDK), in need of suchtreatment a therapeutically effective amount of a compound of thepresent invention (or a pharmaceutical composition thereof). Diseases,conditions, and/or disorders modulated by SGLT2 inhibition include,e.g., type 2 diabetes, diabetic nephropathy, insulin resistancesyndrome, hyperglycemia, hyperinsulinemia, hyperlipidemia, impairedglucose tolerance, obesity (including weight control or weightmaintenance), hypertension, and reducing the level of blood glucose.

Additionally, another aspect of the present invention is directed to amethod for preventing neuronal damage following the incidence ofischemic stroke and close-head traumatic brain injury in animals thatincludes the step of administering to an animal (preferably, a human) inneed of such treatment a therapeutically effective amount of a compoundof the present invention (or a pharmaceutical composition thereof).

In certain embodiments the present invention is directed to a method oftreating prediabetes, type 1 or type 2 diabetes mellitus in a patientcomprising administering ertugliflozin or a co-crystal or apharmaceutically acceptable salt thereof to the patient, wherein thepatient has moderate renal impairment or stage 3 chronic kidney disease(CKD). When used herein, the expression “ertugliflozin or a co-crystalor a pharmaceutically acceptable salt thereof” includes apharmaceutically acceptable salt of ertugliflozin as well as, apharmaceutically acceptable salt of the co-crystal of ertugliflozin. Incertain embodiments, the patient has moderate renal impairment or stage3A chronic kidney disease (CKD). In other embodiments, the patient hasmoderate B renal impairment or stage 3B chronic kidney disease (CKD).

In certain embodiments, ertugliflozin or a co-crystal or apharmaceutically acceptable salt thereof is administered as apharmaceutical composition. In certain embodiments, the pharmaceuticalcomposition comprises 5 mg or 15 mg of ertugliflozin or a co-crystal ora pharmaceutically acceptable salt thereof. In certain embodiments,ertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof is administered once daily.

In other embodiments, the present invention is directed to a method forimproving glycemic control in a patient with type 2 diabetes comprisingadministering ertugliflozin or a co-crystal or a pharmaceuticallyacceptable salt thereof to the patient, wherein the patient has moderaterenal impairment or stage 3 chronic kidney disease (CKD). In certainembodiments, the patient has moderate renal impairment or stage 3Achronic kidney disease (CKD). In other embodiments, the patient hasmoderate B renal impairment or stage 3B chronic kidney disease (CKD). Incertain embodiments, ertugliflozin or a co-crystal or a pharmaceuticallyacceptable salt thereof is administered as a pharmaceutical composition.In certain embodiments, the pharmaceutical composition comprises 5 mg or15 mg of ertugliflozin or a co-crystal or a pharmaceutically acceptablesalt thereof. In certain embodiments, ertugliflozin or a co-crystal or apharmaceutically acceptable salt thereof is administered once daily.

In yet other embodiments, the present invention is direct to a method oftreating prediabetes, type 1 or type 2 diabetes comprising: a)determining the estimated glomerular filtration rate (eGFR) of a patientin need of treatment for prediabetes, type 1 or type 2 diabetes; b)administering ertugliflozin or a co-crystal or a pharmaceuticallyacceptable salt thereof to the patient, if the eGFR of the patient is≥30 ml/min/1.73 m². In certain embodiments, ertugliflozin or aco-crystal or a pharmaceutically acceptable salt thereof is administeredif the eGFR of the patient is between ≥30 ml/min/1.73 m² and <60ml/min/1.73 m². In certain embodiments, ertugliflozin or a co-crystal ora pharmaceutically acceptable salt thereof is administered if the eGFRof the patient is ≥45 ml/min/1.73 m². In certain embodiments,ertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof is administered if the eGFR of the patient is between ≥45ml/min/1.73 m² and <60 ml/min/1.73 m². In certain embodiments,ertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof is administered as a pharmaceutical composition. In certainembodiments, the pharmaceutical composition comprises 5 mg or 15 mg ofertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof. In certain embodiments, ertugliflozin or a co-crystal or apharmaceutically acceptable salt thereof is administered once daily.

In still other embodiments, the present invention is directed to amethod of treating prediabetes, type 1 or type 2 diabetes mellituscomprising: a) determining that the eGFR of a patient in need oftreatment for prediabetes, type 1 or type 2 diabetes is between ≥30ml/min/1.73 m²; b) administering ertugliflozin or a co-crystal or apharmaceutically acceptable salt thereof to the patient. In certainembodiments, the method comprises determining that the eGFR of a patientin need of treatment for prediabetes, type 1 or type 2 diabetes isbetween ≥30 ml/min/1.73 m² and <60 ml/min/1.73 m². In other embodiments,the method comprises a) determining that the eGFR of a patient in needof treatment for prediabetes, type 1 or type 2 diabetes is between ≥45ml/min/1.73 m²; b) administering ertugliflozin or a co-crystal or apharmaceutically acceptable salt thereof to the patient. In yet otherembodiments, the method comprises determining that the eGFR of a patientin need of treatment for prediabetes, type 1 or type 2 diabetes isbetween ≥45 ml/min/1.73 m² and <60 ml/min/1.73 m². In certainembodiments, ertugliflozin or a co-crystal or a pharmaceuticallyacceptable salt thereof is administered as a pharmaceutical composition.In certain embodiments, the pharmaceutical composition comprises 5 mg or15 mg of ertugliflozin or a co-crystal or a pharmaceutically acceptablesalt thereof. In certain embodiments, ertugliflozin or a co-crystal or apharmaceutically acceptable salt thereof is administered once daily.

Other embodiments described herein are directed to a method of loweringurinary albumin excretion in a patient, wherein the patient has moderaterenal impairment or stage 3 chronic kidney disease (CKD). In certainembodiments, the patient has moderate renal impairment or stage 3Achronic kidney disease (CKD). In other embodiments, the patient hasmoderate B renal impairment or stage 3B chronic kidney disease (CKD). Incertain embodiments, ertugliflozin or a co-crystal or a pharmaceuticallyacceptable salt thereof is administered as a pharmaceutical composition.In certain embodiments, the pharmaceutical composition comprises 5 mg or15 mg of ertugliflozin or a co-crystal or a pharmaceutically acceptablesalt thereof. In certain embodiments, ertugliflozin or a co-crystal or apharmaceutically acceptable salt thereof is administered once daily.

In certain embodiments of the methods described herein, the methodresults in decreased blood pressure and decreased uric acid.

Another aspect of the present invention is a pharmaceutical compositionto be used in the methods described that comprises (1) a compound of thepresent invention, and (2) a pharmaceutically acceptable excipient,diluent, or carrier. Preferably, the composition comprises atherapeutically effective amount of a compound of the present invention.The composition may also contain at least one additional pharmaceuticalagent (described herein). Preferred agents include anti-obesity agentsand/or anti-diabetic agents (described herein below).

Also, the methods described herein include compounds described hereinadministered in combination with other pharmaceutical agents (inparticular, anti-obesity and anti-diabetic agents described hereinbelow). The combination therapy may be administered as (a) a singlepharmaceutical composition which comprises a compound of the presentinvention, at least one additional pharmaceutical agent described hereinand a pharmaceutically acceptable excipient, diluent, or carrier; or (b)two separate pharmaceutical compositions comprising (i) a firstcomposition comprising a compound of the present invention and apharmaceutically acceptable excipient, diluent, or carrier, and (ii) asecond composition comprising at least one additional pharmaceuticalagent described herein and a pharmaceutically acceptable excipient,diluent, or carrier. The pharmaceutical compositions may be administeredsimultaneously or sequentially and in any order.

In certain embodiments, the methods described herein includeadministering 5 mg or 15 mg of ertugliflozin or a co-crystal or apharmaceutically acceptable salt thereof in combination with 25 mg or 50mg of sitagliptin or a pharmaceutically acceptable salt thereon. Inother embodiments, the methods described herein include administering 5mg or 15 mg of ertugliflozin or a co-crystal or a pharmaceuticallyacceptable salt thereof in combination with 1000 mg or 2000 mg ofmetformin. In still other embodiments, the methods described hereininclude administering 5 mg or 15 mg of ertugliflozin or a co-crystal ora pharmaceutically acceptable salt thereof in combination with 25 mg or50 mg of sitagliptin or a pharmaceutically acceptable salt thereof and1000 mg or 2000 mg of metformin.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention, as claimed.

DETAILED DESCRIPTION

The present invention may be understood even more readily by referenceto the following detailed description of exemplary embodiments of theinvention and the examples included therein.

Before the present compounds, compositions and methods are disclosed anddescribed, it is to be understood that this invention is not limited tospecific synthetic methods of making that may of course vary. It is alsoto be understood that the terminology used herein is for the purpose ofdescribing particular embodiments only and is not intended to belimiting. The plural and singular should be treated as interchangeable,other than the indication of number:

As used herein, the term “alkyl” refers to a hydrocarbon radical of thegeneral formula C_(n)H_(2n+1). The alkane radical may be straight orbranched. For example, the term “(C₁-C₆)alkyl” refers to a monovalent,straight, or branched aliphatic group containing 1 to 6 carbon atoms(e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl,t-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,neopentyl, 3,3-dimethylpropyl, hexyl, 2-methylpentyl, and the like).Similarly, the alkyl portion (i.e., alkyl moiety) of an alkoxy, acyl(e.g., alkanoyl), alkylamino, dialkylamino, alkylsulfonyl, and alkylthiogroup have the same definition as above. When indicated as being“optionally substituted”, the alkane radical or alkyl moiety may beunsubstituted or substituted with one or more substituents (generally,one to three substituents except in the case of halogen substituentssuch as perchloro or perfluoroalkyls) independently selected from thegroup of substituents listed below in the definition for “substituted.”“Halo-substituted alkyl” refers to an alkyl group substituted with oneor more halogen atoms (e.g., fluoromethyl, difluoromethyl,trifluoromethyl, perfluoroethyl, 1,1-difluoroethyl and the like).

The term “cycloalkyl” refers to nonaromatic rings and may exist as asingle ring, bicyclic ring or a spiro ring. Unless specified otherwise,the carbocyclic ring is generally a 3- to 8-membered ring. For example,cycloalkyl include groups such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclohexenyl, norbornyl (bicyclo[2.2.1]heptyl),bicyclo[2.2.2]octyl, and the like.

The term “heterocycle” refers to nonaromatic rings and may exist as asingle ring, bicyclic ring or a spiral ring. Unless specified otherwise,the heterocyclic ring is generally a 3- to 6-membered ring containing 1to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selectedfrom sulfur, oxygen and/or nitrogen. Heterocyclic rings include groupssuch as epoxy, aziridinyl, tetrahydrofuranyl, pyrrolidinyl,N-methylpyrrolidinyl, piperidinyl, piperazinyl, pyrazolidinyl,4H-pyranyl, morpholino, thiomorpholino, tetrahydrothienyl,tetrahydrothienyl 1,1-dioxide, and the like.

The phrase “therapeutically effective amount” means an amount of acompound of the present invention that (i) treats the particulardisease, condition, or disorder, (ii) attenuates, ameliorates, oreliminates one or more symptoms of the particular disease, condition, ordisorder, or (iii) prevents or delays the onset of one or more symptomsof the particular disease, condition, or disorder described herein.

The term “animal” refers to humans (male or female), companion animals(e.g., dogs, cats and horses), food-source animals, zoo animals, marineanimals, birds and other similar animal species.

The phrase “pharmaceutically acceptable” indicates that the substance orcomposition must be compatible chemically and/or toxicologically, withthe other ingredients comprising a formulation, and/or the mammal beingtreated therewith.

The terms “treating”, “treat”, or “treatment” embrace both preventative,i.e., prophylactic, and palliative treatment.

The terms “modulated” or “modulating”, or “modulate(s)”, as used herein,unless otherwise indicated, refers to the inhibition of thesodium-glucose transporter (in particular, SGLT2) with compounds of thepresent invention thereby partially or fully preventing glucosetransport across the transporter.

The term “preventing”, as used herein, unless otherwise indicated,refers to reducing the likelihood or severity of neuronal damagefollowing the incidence of ischemic stroke and close-head traumaticbrain injury.

The term “compounds of the present invention” (unless specificallyidentified otherwise) refer to compounds of Formula (A), Formula (B) andall pure and mixed stereoisomers (including diastereoisomers andenantiomers), tautomers and isotopically labeled compounds. Hydrates andsolvates of the compounds of the present invention are consideredcompositions of the present invention, wherein the compound is inassociation with water or solvent, respectively. The compounds may alsoexist in one or more crystalline states, i.e. as co-crystals,polymorphs, or they may exist as amorphous solids. All such forms areencompassed by the claims.

In one embodiment, R¹ is H, methyl, ethyl, propyl, isopropyl, methoxy,ethoxy, F, Cl, cyano, —CF₃, cyclopropyl, or cyclobutyl. In anotherembodiment, R¹ is H, methyl, ethyl, isopropyl, methoxy, ethoxy, F, Cl,cyano, —CF₃, or cyclopropyl. In a further embodiment, R¹ is H, methyl,ethyl, methoxy, ethoxy, F, Cl, cyano, —CF₃, or cyclopropyl. In yet afurther embodiment, R¹ is methyl, ethyl, F, Cl, cyano, CF₃, orcyclopropyl.

In one embodiment, R² is methyl, ethyl, propyl, isopropyl, methoxy,ethoxy, F, Cl, cyano, —CF₃, —CF₂CH₃, ethynyl, 3-oxetanyloxy,3-tetrahydrofuranyloxy, or cyclopropyl. In another embodiment, R² ismethyl, ethyl, isopropyl, methoxy, ethoxy, F, Cl, cyano, —CF₃, —CF₂CH₃,ethynyl, 3-oxetanyloxy, 3-tetrahydrofuranyloxy, or cyclopropyl. In afurther embodiment, R² is methyl, ethyl, methoxy, ethoxy, F, Cl, cyano,—CF₃, —CF₂CH₃, ethynyl, 3-oxetanyloxy, 3-tetrahydrofuranyloxy, orcyclopropyl. In yet a further embodiment, R² is methoxy or ethoxy.

“Ertugliflozin” means the compound of formula (4A):

and has the chemical name having the chemical name(1S,2S,3S,4R,5S)-5-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-1-hydroxymethyl-6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triol.In certain embodiments of the methods described herein ertugliflozin canexist as a co-crystal or a pharmaceutically acceptable salt.

In one embodiment, the crystal comprises the compound 4A and L-prolineor L-pyroglutamic acid.

In a further embodiment, the crystal has one or more of the following:

-   -   a) space group of P2(1)2(1)2(1) and unit cell parameters        substantially equal to the following:        -   a=7.4907(10) Å α=90°.        -   b=12.8626(15) Å β=90°.        -   c=28.029(4) Å γ=90°;    -   b) a powder x-ray diffraction pattern comprising 2-theta values        of (CuKα radiation, wavelength of 1.54056 Å) 6.4±0.2, 16.7±0.2,        17.4±0.2 and 21.1±0.2;    -   c) a solid state 13C NMR spectrum having peak positions at        16.5±0.2, 131.1±0.2, 158.7±0.2, and 181.5±0.2 ppm as determined        on a 500 MHz spectrometer relative to crystalline adamantine of        29.5 ppm; or    -   d) a differential scanning calorimetry thermogram having an        endotherm of about 142.5±2° C.

In a further embodiment, the crystal is a co-crystal comprising thecompound of formula (4A) and L-pyroglutamic acid in a 1:1 stochiometricratio.

The term “glomerular filtration rate (GFR)” refers to the volume offluid filtered from the renal (kidney) glomerular capillaries into theBowman's capsule per unit time. It is indicative of overall kidneyfunction. The glomerular filtration rate (GFR) can be calculated bymeasuring any chemical that has a steady level in the blood, and isfreely filtered but neither reabsorbed nor secreted by the kidneys. Therate therefore measured is the quantity of the substance in the urinethat originated from a calculable volume of blood. The GFR is typicallyrecorded in units of volume per time, e.g., milliliters per minute andthe formula below can be used:GFR=(Urine Concentration.times.Urine Volume)/Plasma Concentration

The GFR can be determined by injecting inulin into the plasma. Sinceinulin is neither reabsorbed nor secreted by the kidney after glomerularfiltration, its rate of excretion is directly proportional to the rateof filtration of water and solutes across the glomerular filter. Anormal value is: GFR=90-125 mL/min/1.73 m², in particular GFR=100-125mL/min/1.73 m². Other principles to determine GFR involve measuring51Cr-EDTA, iothalamate or iohexol.

The phrase “estimated glomerular filtration rate (eGFR)” is derived atscreening from serum creatinine values based on e.g., the Chronic KidneyDisease Epidemiology Collaboration (CKD-EPI) equation, theCockcroft-Gault formula or the Modification of Diet in Renal Disease(MDRD) formula, which are all known in the art.

Compounds used in the methods of the present invention may besynthesized by synthetic routes that include processes analogous tothose well-known in the chemical arts, particularly in light of thedescription contained herein. The starting materials are generallyavailable from commercial sources such as Aldrich Chemicals (Milwaukee,Wis.) or are readily prepared using methods well known to those skilledin the art (e.g., prepared by methods generally described in Louis F.Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley,New York. (1967-1999 ed.), or Beilsteins Handbuch der organischenChemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements(also available via the Beilstein online database)).

For illustrative purposes, the reaction schemes depicted below providepotential routes for synthesizing the compounds of the present inventionas well as key intermediates. Those skilled in the art will appreciatethat other synthetic routes may be used to synthesize the inventivecompounds. Although specific starting materials and reagents aredepicted in the schemes and discussed below, other starting materialsand reagents can be easily substituted to provide a variety ofderivatives and/or reaction conditions. In addition, many of thecompounds prepared by the methods described below can be furthermodified in light of this disclosure using conventional chemistry wellknown to those skilled in the art.

In the preparation of compounds of the present invention, protection ofremote functionality of intermediates may be necessary. The need forsuch protection will vary depending on the nature of the remotefunctionality and the conditions of the preparation methods. A“hydroxy-protecting group” refers to a substituent of a hydroxy groupthat blocks or protects the hydroxy functionality. Suitablehydroxyl-protecting groups (O-Pg) include for example, allyl, acetyl(Ac), silyl (like trimethylsily (TMS) or tert-butyldimethylsilyl (TBS)),benzyl (Bn), para-methoxybenzyl (PMB), trityl (Tr), para-bromobenzoyl,para-nitrobenzoyl and the like (benzylidene for protection of1,3-diols). The need for such protection is readily determined by oneskilled in the art. For a general description of protecting groups andtheir use, see T. W. Greene, Protective Groups in Organic Synthesis,John Wiley & Sons, New York, 1991.

Scheme 1 outlines the general procedures one could use to providecompounds of the present invention.

Allyl 2,3,4-tri-O-benzyl-D-glucopyranoside (I-a, where Pg¹ is a benzylgroup) can be prepared by procedures described by Shinya Hanashima, etal., in Bioorganic & Medicinal Chemistry, 9, 367 (2001); Patricia A.Gent et al. in Journal of the Chemical Society, Perkin 1, 1835 (1974);Hans Peter Wessel in the Journal of Carbohydrate Chemistry, 7, 263,(1988); or Yoko Yuasa, et al., in Organic Process Research &Development, 8, 405-407 (2004). In step 1 of Scheme 1, thehydroxymethylene group can be introduced onto the glycoside by means ofa Swern oxidation followed by treatment with formaldehyde in thepresence of an alkali metal hydroxide (e.g., sodium hydroxide). This isreferred to as an aldol-Cannizzaro reaction. The Swern oxidation isdescribed by Kanji Omura and Daniel Swern in Tetrahedron, 34, 1651(1978). Modifications of this process known to those of skill in the artmay also be used. For example, other oxidants, like stabilized2-iodoxybenzoic acid described by Ozanne, A. et al. in Organic Letters,5, 2903 (2003), as well as other oxidants known by those skilled in theart can also be used. The aldol Cannizzaro sequence has been describedby Robert Schaffer in the Journal of The American Chemical Society, 81,5452 (1959) and Amigues, E. J., et al., in Tetrahedron, 63, 10042(2007).

In step 2 of Scheme 1, protecting groups (Pg²) can be added by treatingintermediate (I-b) with the appropriate reagents and procedures for theparticular protecting group desired. For example, p-methoxybenzyl (PMB)groups may be introduced by treatment of intermediate (I-b) withp-methoxybenzyl bromide or p-methoxybenzyl chloride in the presence ofsodium hydride, potassium hydride, potassium tert-butoxide in a solventlike tetrahydrofuran, 1,2-dimethoxyethane or N,N-dimethylformamide(DMF). Conditions involving para-methoxybenzyltrichloroacetimidate inpresence of a catalytic amount of acid (e.g., trifluoromethanesulfonicacid, methanesulfonic acid, or camphorsulfonic acid) in a solvent suchas dichloromethane, heptane or hexanes can also be used. Benzyl (Bn)groups may be introduced by treatment of intermediate (I-b) with benzylbromide or benzyl chloride in the presence of sodium hydride, potassiumhydride, potassium tert-butoxide in a solvent like tetrahydrofuran,1,2-dimethoxyethane or N,N-dimethylformamide. Conditions involvingbenzyltrichloroacetimidate in presence of a catalytic amount of acid(e.g., trifluoromethanesulfonic acid, methanesulfonic acid, orcamphorsulfonic acid) in a solvent such as dichloromethane, heptane orhexanes can also be used.

In step 3 of Scheme 1, the allyl protection group is removed (e.g., bytreatment with palladium chloride in methanol; cosolvent likedichloromethane may also be used; other conditions known by thoseskilled in the art could also be used, see T. W. Greene, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, New York, 1991) to formthe lactol (I-d).

In step 4 of Scheme 1, oxidation of the unprotected hydroxyl group to anoxo group (e.g., Swern oxidation) then forms the lactone (I-e).

In step 5 of Scheme 1, the lactone (I-e) is reacted with N, O-dimethylhydroxylamine hydrochloride to form the corresponding Weinreb amidewhich may exist in equilibrium in a closed/opened form. (I-f/I-g). The“Weinreb amide” (I-g) can be made using procedures well known to thoseof skill in the art. See, Nahm, S., and S. M. Weinreb, TetrahedronLetters, 22 (39), 3815-1818 (1981). For example, intermediate (I-f/I-g)can be prepared from the commercially availableN,O-dimethylhydroxylamine hydrochloride and an activating agent (e.g.,trimethylaluminum).

In step 6 of Scheme 1, the aryl benzyl group (Ar) is introduced usingthe desired organometallic reagent (e.g., organo lithium compound (ArLi)or organomagnesium compound (ArMgX)) in tetrahydrofuran (THF) at atemperature ranging from about −78° C. to about 20° C. followed byhydrolysis (upon standing in protic conditions) to the correspondinglactol (I-i) which may be in equilibrium with the corresponding ketone(I-h). The bridged ketal motif found in (A) and (B) can be prepared byremoving the protecting groups (Pg²) using the appropriate reagents forthe protecting groups employed. For example, the, p-methoxybenzyl (PMB)protecting groups may be removed by treatment with trifluoroacetic acidin the presence of anisole and dichloromethane (DCM) at about 0° C. toabout 23° C. (room temperature). The remaining protecting groups (Pg¹)may then be removed using the appropriate chemistry for the particularprotecting groups. For example, benzyl protecting groups may be removedby treating with formic acid in the presence of palladium (Pd black) ina protic solvent (e.g., ethanol/THF) at about room temperature toproduce the final products (A) and (B). When R¹ is CN, the use of aLewis acid like boron trichloride at a temperature ranging from about−78° C. to about room temperature in a solvent like dichloromethane or1,2-dichloroethane may also be used to remove benzyl protective and/orpara-methoxybenzyl protective groups.

When R¹ is CN and R² is (C₁-C₄)alkoxy in intermediate (I-i) or inproducts (A) or (B), upon treatment with a Lewis acid such as borontrichloride or boron tribomide, partial to complete de-alkylation to thecorresponding phenol may occur to lead to the corresponding compound (A)or (B) where R¹ is CN and R² is OH. If this occurs, the (C₁-C₄)alkoxygroup may be re-introduced via selective alkylation using a (C₁-C₄)alkyl iodide under mildly basic conditions, for example, potassiumcarbonate in acetone at a temperature ranging from about roomtemperature to about 56 degrees Celsius.

When R¹ and/or R² is (C₁-C₄)alkyl-SO₂— it is understood by one skilledin the art that the organometallic addition step 6 (Scheme 1) will becarried out on the corresponding (C₁-C₄)alkyl-S— containingorganometallic reagent. The thio-alkyl is then oxidized at a later stageto the corresponding sulfone using conventional methods known by thoseskilled in the art.

The compounds of the present invention may be prepared as co-crystalsusing any suitable method. A representative scheme for preparing suchco-crystals is described in Scheme 2.

In Scheme 2, wherein Me is methyl and Et is ethyl, in step 1,1-(5-bromo-2-chlorobenzyl)-4-ethoxybenzene is dissolved in 3:1, toluene:tetrahydrofuran followed by cooling the resulting solution to <−70° C.To this solution is added hexyllithium while maintaining the reaction at≤−65° C. followed by stirring for 1 hour.(3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)-tetrahydropyran-2-one(II-a) is dissolved in toluene and the resulting solution is cooled to−15° C. This solution is then added to the −70° C. aryllithium solutionfollowed by stirring for 1 hour. A solution of methanesulfonic acid inmethanol is then added followed by warming to room temperature andstirring for 16 to 24 hours. The reaction is deemed complete when theα-anomer level is ≤3%. The reaction is then basified by the addition of5 M aqueous sodium hydroxide solution. The resulting salts are filteredoff followed by concentration of the crude product solution.2-methyltetrahydrofuran is added as a co-solvent and the organic phaseis extracted twice with water. The organic phase is then concentrated to4 volumes in toluene. This concentrate is then added to a 5:1, heptane:toluene solution causing precipitate to form. The solids are collectedand dried under vacuum to afford a solid.

In step 2 of Scheme 2, to (II-b) in methylene chloride is addedimidazole followed by cooling to 0° C. and then addition oftrimethylsilylchloride to give the persilylated product. The reaction iswarmed to room temperature and quenched by the addition of water, andthe organic phase is washed with water. This crude methylene chloridesolution of (II-c) is dried over sodium sulfate and then taken on crudeinto the next step.

In step 3 of Scheme 2, the crude solution of (II-c) in methylenechloride is concentrated to low volume and then the solvent is exchangedto methanol. The methanol solution of (II-c) is cooled to 0° C., then 1mol % of potassium carbonate is added as a solution in methanol followedby stirring for 5 hours. The reaction is then quenched by addition of 1mol % acetic acid in methanol, followed by warming to room temperature,solvent exchange to ethyl acetate, and then filtration of the minoramount of inorganic solids. The crude ethyl acetate solution of (II-d)is taken directly into the next step.

In step 4 of Scheme 2, the crude solution of (II-d) is concentrated tolow volume, then diluted with methylene chloride and dimethylsulfoxide.Triethylamine is added followed by cooling to 10° C. and then sulfurtrioxide pyridine complex is added in 3 portions as a solid at 10 minuteintervals. The reaction is stirred an additional 3 hours at 10° C.before quenching with water and warming to room temperature. The phasesare separated followed by washing the methylene chloride layer withaqueous ammonium chloride. The crude methylene chloride solution of(II-e) is taken directly into the next step.

In step 5 of Scheme 2, the crude solution of (II-e) is concentrated tolow volume and then the solvent is exchanged to ethanol. Thirtyequivalents of aqueous formaldehyde is added followed by warming to 55°C. An aqueous solution of 2 equivalents of potassium phosphate, tribasicis added followed by stirring for 24 hours at 55° C. The reactiontemperature is then raised to 70° C. for an additional 12 hours. Thereaction is cooled to room temperature, diluted with tert-butyl methylether and brine. The phases are separated followed by solvent exchangeof the organic phase to ethyl acetate. The ethyl acetate phase is washedwith brine and concentrated to low volume. The crude concentrate is thenpurified by silica gel flash chromatography eluting with 5% methanol,95% toluene. Product containing fractions are combined and concentratedto low volume. Methanol is added followed by stirring untilprecipitation occurs. The suspension is cooled and the solids arecollected and rinsed with heptane followed by drying. Product (II-f) isisolated as a solid.

In step 6 of Scheme 2, compound (II-f) is dissolved in 5 volumes ofmethylene chloride followed by the addition of 1 mol % SiliaBond® tosicacid and stirring for 18 hours at room temperature. The acid catalyst isfiltered off and the methylene chloride solution of (II-g) is takendirectly into the next step co-crystallization procedure.

In step 7 of Scheme 2, the methylene chloride solution of (II-g) isconcentrated and then the solvent is exchanged to 2-propanol. Water isadded followed by warming to 55° C. An aqueous solution ofL-pyroglutamic acid is added followed by cooling the resulting solutionto room temperature. The solution is then seeded and granulated for 18hours. After cooling, the solids are collected and rinsed with heptanefollowed by drying. Product (II-h) is isolated as a solid.

An alternative synthesis route for compounds (A) of the presentinvention is depicted in Scheme 3 and described below.

The synthesis of (III-a), where R₃ is an alkyl or fluoro substitutedalkyl (except for the carbon adjacent to the oxygen atom) can beprepared in a similar way as described in step 1 of Scheme 2. In step 1of Scheme 3, the primary hydroxyl group is selectively protected by anappropriate protective group. For example, a trityl group (Pg₃=Tr) canbe introduced by treatment of intermediate (III-a) withchlorotriphenylmethane in presence of a base like pyridine in a solventlike toluene, tetrahydrofuran or dichloromethane at a temperatureranging from about 0 degrees Celsius to about room temperature.Additional examples of such protective groups and experimentalconditions are known by those skilled in the art and can be found in T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons,New York, 1991.

In step 2 of Scheme 3, the secondary hydroxyl groups can be protected bythe appropriate protecting groups. For example, benzyl groups (Pg₄ isBn) can be introduced by treatment of intermediate (III-b) with benzylbromide or benzyl chloride in the presence of sodium hydride, potassiumhydride, potassium tert-butoxide in a solvent like tetrahydrofuran,1,2-dimethoxyethane or N,N-dimethylformamide at a temperature rangingfrom about 0 degrees Celsius to about 80 degrees Celsius. Acetyl orbenzoyl groups (Pg₄=Ac or Bz) may be introduced by treatment ofintermediate (III-b) with acetyl chloride, acetyl bromide or aceticanhydride or benzoyl chloride or benzoic anhydride in the presence of abase like triethylamine, N,N-diisopropylethylamine or4-(dimethylamino)pyridine in a solvent like tetrahydrofuran,1,2-dimethoxyethane or dichloromethane at a temperature ranging fromabout 0 degrees Celsius to about 80 degrees Celsius.

In step 3 of Scheme 3, the primary hydroxyl group is deprotected to leadto intermediate (III-d). When Pg₃ is Tr, intermediate (III-c) is treatedin the presence of an acid like para-toluenesulfonic acid in analcoholic solvent like methanol at a temperature ranging from about −20degrees Celsius to about room temperature to provide intermediate(III-d). Cosolvents like chloroform may be used.

In step 4 of Scheme 3, a hydroxymethylene group is introduced through aprocess similar to the one already described in Scheme 1 (step 1) andScheme 2 (steps 4 and 5). Other sources of formaldehyde, likeparaformaldehyde in a solvent like ethanol at a temperature ranging fromabout room temperature to about 70 degrees Celsius in the presence of analkali metal alkoxide can also be used in this step. When Pg₄ is Bn,this step provides intermediate (III-e) and when Pg₄ is Ac or Bz, thisstep provides intermediate (III-f).

In step 5 of Scheme 3, intermediate (III-e) is treated with an acid liketrifluoroacetic acid or an acidic resin in a solvent likedichloromethane at a temperature ranging from about −10 degrees Celsiusto about room temperature to produce intermediate (III-g).

In step 6 of Scheme 3, the remaining protecting groups (Pg₄) may then beremoved using the appropriate chemistry for the particular protectinggroups. For example, benzyl protecting groups may be removed by treatingwith formic acid in the presence of palladium (Pd black) in a proticsolvent (e.g., ethanol/THF) at about room temperature to produce thefinal product (A).

In step 7 of Scheme 3, intermediate (III-f) is treated with an acid liketrifluoroacetic acid or an acidic resin in a solvent likedichloromethane at a temperature ranging from about −10 degrees Celsiusto about room temperature to produce the final product (A).

Another alternative scheme for synthesizing product (A) is depicted inScheme 4 and described below.

In step 1 of Scheme 4, intermediate (III-a) is treated with theappropriate arylsulfonyl chloride R₄SO₂Cl or arylsulfonic anhydrideR₄S(O)₂OS(O)₂R₄ (wherein R₄ is an optionally substituted aryl group,such as found in the arylsulfonyl chlorides 4-methyl-benzenesulfonylchloride, 4-nitro-benzenesulfonyl chloride, 4-fluoro-benzenesulfonylchloride, 2,6-dichloro-benzenesulfonyl chloride,4-fluoro-2-methyl-benzenesulfonyl chloride, and2,4,6-trichloro-benzenesulfonyl chloride, and in the arylsulfonicanhydride, p-toluenesulfonic anhydride) in presence of a base likepyridine, triethylamine, N,N-diisopropylethylamine in a solvent liketetrahydrofuran, 2-methyltetrahydrofuran at a temperature ranging fromabout −20 degrees Celsius to about room temperature. Some Lewis acidslike zinc(II) bromide may be used as additives.

In step 2 of Scheme 4, intermediate (IV-a) is submitted to aKornblum-type oxidation (see, Kornblum, N., et al., Journal of TheAmerican Chemical Society, 81, 4113 (1959)) to produce the correspondingaldehyde which may exist in equilibrium with the corresponding hydrateand/or hemiacetal form. For example intermediate (IV-a) is treated inthe presence of a base like pyridine, 2,6-lutidine, 2,4,6-collidine,N,N-diisopropylethylamine, 4-(dimethylamino) pyridine in a solvent likedimethyl sulfoxide at a temperature ranging from about room temperatureto about 150 degrees Celsius. The aldehyde intermediate produced is thensubmitted to the aldol/Cannizzaro conditions described for step 1(Scheme 1) and step 5 (Scheme 2) to produce intermediate (IV-b).

In step 3 of Scheme 4, intermediate (IV-b) is treated with an acid liketrifluoroacetic acid or an acidic resin in a solvent likedichloromethane at a temperature ranging from about −10 degrees Celsiusto about room temperature to produce the final product (A).

When R² is (C₂-C₄)alkynyl the process may be performed using Scheme 5,wherein R⁶ is H or (C₁-C₂)alkyl.

In step 1 of Scheme 5, which provides intermediate (V-i), theorganometallic addition step is carried out in a similar way to the onedescribed in Scheme 1, step 6, using the organometallic reagent derivedfrom (V-a), where Pg₅ is a suitable protective group for the hydroxylgroup. For instance Pg₅ can be a tert-butyldimethylsilyl group (TBS)(see US2007/0054867 for preparation of for instance{4-[(5-bromo-2-chloro-phenyl)-methyl]-phenoxy}-tert-butyl-dimethyl-silane).

In step 2 of Scheme 5, when Pg²=PMB, intermediate (V-i) is treated withan acid like trifluoroacetic acid, methanesulfonic acid or an acidicresin in presence of anisole in a solvent like dichloromethane at atemperature ranging from about −10 degrees Celsius to about roomtemperature to produce intermediate (V-j).

In step 3 of Scheme 5, protecting groups (Pg₅) and (Pg¹) can be removedto provide (V-k). Typically (Pg₅) is TBS and Pg¹ is Bn. In thiscircumstance, the protecting groups are removed by sequential treatmentof (V-j) with 1) tetrabutylammonium fluoride in a solvent liketetrahydrofuran or 2-methyltetrahydrofuran at a temperature ranging from0 degrees Celsius to about 40 degrees Celsius and 2) treatment withformic acid in the presence of palladium (Pd black) in a protic solvent(e.g., ethanol/THF) at about room temperature. In this sequence, theorder of the 2 reactions is interchangeable.

In step 4 of Scheme 5, intermediate (V-k) is treated withN,N-bis-(trifluoromethanesulfonyl)-aniline in presence of a base liketriethylamine or 4-dimethyaminopyridine in a solvent likedichloromethane or 1,2-dichloroethane at a temperature ranging from 0degrees Celsius to about 40 degrees Celsius to produce intermediate(V-l).

In step 5 of Scheme 5, intermediate (V-l) is subjected to aSonogashira-type reaction (see, Sonogashira, K. Coupling ReactionsBetween sp² and sp Carbon Centers. In Comprehensive Organic Synthesis(eds. Trost, B. M., Fleming, I.), 3, 521-549, (Pergamon, Oxford, 1991)).For instance (V-l) is treated with the appropriate terminal alkyne HCCR⁶in presence of copper(I) iodide, a catalyst likebis-(triphenylphosphine)-palladium dichloride ortetrakis(triphenylphosphine)palladium(0) in presence of a base liketriethylamine or N,N-diisopropylethylamine in a solvent likeN,N-dimethylformamide at a temperature ranging from about roomtemperature to about 120 degrees Celsius to produce the desired product(A) and (B). When R⁶ is H, it is more convenient to usetrimethylsilylacetylene. In this case the crude material obtained fromthe reaction described above is treated with a base like potassiumcarbonate in an alcoholic solvent like MeOH at about room temperature toproduce after classical work-up known by those skilled in the art thedesired product (A) and (B) where R² is —CCH.

One skilled in the art would understand that the chemistry describedabove in schemes 1 to 5, represents different ways of accessingintermediate (V-k). In turn, particularly when R¹ is Cl, (V-k) can betreated with an alkylating agent of choice under classical conditions toselectively alkylate the phenol group to produce (A) (and (B) in schemes1 and 5) where R² is (C₁-C₄)alkoxy.

The compounds of the present invention contain asymmetric or chiralcenters, and, therefore, exist in different stereoisomeric forms. Unlessspecified otherwise, it is intended that all stereoisomeric forms of thecompounds of the present invention as well as mixtures thereof,including racemic mixtures, form part of the present invention. Inaddition, the present invention embraces all geometric and positionalisomers. For example, if a compound of the present inventionincorporates a double bond or a fused ring, both the cis- andtrans-forms, as well as mixtures, are embraced within the scope of theinvention.

Diastereomeric mixtures can be separated into their individualdiastereoisomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as bychromatography and/or fractional crystallization, distillation,sublimation. Enantiomers can be separated by converting the enantiomericmixture into a diastereomeric mixture by reaction with an appropriateoptically active compound (e.g., chiral auxiliary such as a chiralalcohol or Mosher's acid chloride), separating the diastereoisomers andconverting (e.g., hydrolyzing) the individual diastereoisomers to thecorresponding pure enantiomers. Also, some of the compounds of thepresent invention may be atropisomers (e.g., substituted biaryls) andare considered as part of this invention. Enantiomers can also beseparated by use of a chiral HPLC (high pressure liquid chromatography)column.

It is also possible that the intermediates and compounds of the presentinvention may exist in different tautomeric forms, and all such formsare embraced within the scope of the invention. The term “tautomer” or“tautomeric form” refers to structural isomers of different energieswhich are interconvertible via a low energy barrier. For example, protontautomers (also known as prototropic tautomers) include interconversionsvia migration of a proton, such as keto-enol and imine-enamineisomerizations. A specific example of a proton tautomer is the imidazolemoiety where the proton may migrate between the two ring nitrogens.Valence tautomers include interconversions by reorganization of some ofthe bonding electrons. The equilibrium between closed and opened form ofsome intermediates (and/or mixtures of intermediates) is reminiscent ofthe process of mutarotation involving aldoses, known by those skilled inthe art.

The present invention also embraces isotopically-labeled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S,¹⁸F, ¹²³I, ¹²⁵I and ³⁶Cl, respectively.

Certain isotopically-labeled compounds of the present invention (e.g.,those labeled with ³H and ¹⁴C) are useful in compound and/or substratetissue distribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e.,¹⁴C) isotopes are particularly preferred for their ease of preparationand detectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Positron emitting isotopes such as ¹⁵O, ¹³N, ¹¹C, and ¹⁸Fare useful for positron emission tomography (PET) studies to examinesubstrate occupancy. Isotopically labeled compounds of the presentinvention can generally be prepared by following procedures analogous tothose disclosed in the Schemes and/or in the Examples herein below, bysubstituting an isotopically labeled reagent for a non-isotopicallylabeled reagent.

The compounds described herein are used in the methods of the presentinvention for treating diseases, conditions and/or disorders modulatedby the inhibition of the sodium-glucose transporters (in particularSGLT2) in patients with renal impairment or chronic kidney disease(CDK).

The present invention provides a method of treating diseases, conditionsand/or disorders modulated by the inhibition of sodium-glucosetransporters in an animal with renal impairment or chronic kidneydisease (CDK) that includes administering to an animal in need of suchtreatment a therapeutically effective amount of a compound describedherein or a pharmaceutical composition comprising an effective amount ofa compound described herein and a pharmaceutically acceptable excipient,diluent, or carrier. The method is particularly useful for treatingdiseases, conditions and/or disorders that benefit from the inhibitionof SGLT2.

In certain embodiments, the patients which may be amenable to thetherapies of this invention may have or are at-risk for one or more ofthe following diseases, disorders or conditions: type 1 diabetes, type 2diabetes, impaired glucose tolerance (IGT), impaired fasting bloodglucose (IFG), hyperglycemia, postprandial hyperglycemia, postabsorptivehyperglycemia, latent autoimmune diabetes in adults (LADA), overweight,obesity, dyslipidemia, hyperlipidemia, hypercholesterolemia,hypertriglyceridemia, hyperNEFA-emia, postprandial lipemia,hypertension, atherosclerosis, endothelial dysfunction, osteoporosis,chronic systemic inflammation, nonalcoholic fatty liver disease (NAFLD),polycystic ovarian syndrome, metabolic syndrome, nephropathy, micro- ormacroalbuminuria, proteinuria, retinopathy, cataracts, neuropathy,learning or memory impairment, neurodegenerative or cognitive disorders,cardiovascular diseases, tissue ischaemia, diabetic foot or ulcus,atherosclerosis, hypertension, endothelial dysfunction, myocardialinfarction, acute coronary syndrome, unstable angina pectoris, stableangina pectoris, peripheral arterial occlusive disease, cardiomyopathy(including e.g. uremic cardiomyopathy), heart failure, cardiachypertrophy, heart rhythm disorders, vascular restenosis, stroke,(renal, cardiac, cerebral or hepatic) ischemia/reperfusion injuries,(renal, cardiac, cerebral or hepatic) fibrosis, (renal, cardiac,cerebral or hepatic) vascular remodeling; a diabetic disease, especiallytype 2 diabetes, mellitus may be preferred (e.g. as underlying disease).

In one embodiment, the present invention provides a method for usingertugliflozin in one or more of the following methods: preventing,slowing the progression of, delaying or treating a metabolic disorderselected from the group consisting of type 2 diabetes mellitus, impairedglucose tolerance, impaired fasting blood glucose, hyperglycemia,postprandial hyperglycemia, hyperinsulinemia and metabolic syndrome; orslowing the progression of, delaying or treating of pre-diabetes; orpreventing, slowing the progression of, delaying or treating of an onsetof type 2 diabetes mellitus; or improving glycemic control and/or forreducing of fasting plasma glucose, of postprandial plasma glucoseand/or of glycosylated hemoglobin HbA1c; or preventing, slowing,delaying or reversing progression from impaired glucose tolerance,impaired fasting blood glucose, insulin resistance or from metabolicsyndrome to type 2 diabetes mellitus; or preventing, slowing theprogression of, delaying or treating of a condition or disorder selectedfrom the group consisting of complications of diabetes mellitus such ascataracts and micro- and macrovascular diseases, such as nephropathy,retinopathy, neuropathy, tissue ischaemia, diabetic foot, dyslipidemia,arteriosclerosis, myocardial infarction, acute coronary syndrome,unstable angina pectoris, stable angina pectoris, stroke, peripheralarterial occlusive disease, cardiomyopathy, heart failure, heart rhythmdisorders and vascular restenosis; or reducing body weight and/or bodyfat, or preventing an increase in body weight and/or body fat, orfacilitating a reduction in body weight and/or body fat; or preventing,slowing, delaying or treating the degeneration of pancreatic beta cellsand/or the decline of the functionality of pancreatic beta cells and/orfor improving and/or restoring the functionality of pancreatic betacells and/or restoring the functionality of pancreatic insulinsecretion; or preventing, slowing, delaying or treating diseases orconditions attributed to an abnormal accumulation of ectopic fat, inparticular liver fat; or for maintaining and/or improving the insulinsensitivity and/or for treating or preventing hyperinsulinemia and/orinsulin resistance; in a patient with renal impairment or chronic kidneydisease (CDK), in particular a patient with mild or moderate renalimpairment.

In one embodiment, the method comprises treating prediabetes, type 1 ortype 2 diabetes mellitus. In one embodiment, the method comprisesimproving glycemic control in a patient with prediabetes, type 1 or type2 diabetes mellitus.

In one embodiment, the present invention provides a method of treatingprediabetes, type 1 or type 2 diabetes mellitus in patient comprisingadministering ertugliflozin or a co-crystal or a pharmaceuticallyacceptable salt thereof to the patient, wherein the patient has moderaterenal impairment. In one embodiment, the patient has moderate A renalimpairment. In one embodiment, the patient has moderate B renalimpairment.

In one embodiment, the present invention further provides a method forimproving glycemic control in a patient with prediabetes, type 1 or type2 diabetes mellitus comprising administering ertugliflozin or aco-crystal or a pharmaceutically acceptable salt thereof to the patient,wherein the patient has moderate renal impairment. In one embodiment,the patient has moderate A renal impairment. In one embodiment, thepatient has moderate B renal impairment.

In one embodiment, the present invention further provides a method oftreating prediabetes, type 1 or type 2 diabetes mellitus in patientcomprising administering ertugliflozin or a co-crystal or apharmaceutically acceptable salt thereof to the patient, wherein thepatient has stage 3 chronic kidney disease (CKD). In one embodiment, thepatient has stage 3A chronic kidney disease (CKD). In one embodiment,the patient has stage 3B chronic kidney disease (CKD).

In one embodiment, the present invention further provides a method forimproving glycemic control in a patient with prediabetes, type 1 or type2 diabetes mellitus comprising administering ertugliflozin or aco-crystal or a pharmaceutically acceptable salt thereof to the patient,wherein the patient has stage 3 chronic kidney disease (CKD). In oneembodiment, the patient has stage 3A chronic kidney disease (CKD). Inone embodiment, the patient has stage 3B chronic kidney disease (CKD).

In one embodiment, the present invention further provides a method oftreating prediabetes, type 1 or type 2 diabetes mellitus or improvingglycemic control in a patient with prediabetes, type 1 or type 2diabetes mellitus, said method comprising: a) assessing the renalfunction of a patient; b) treating a patient having moderate renalimpairment with ertugliflozin or a co-crystal or a pharmaceuticallyacceptable salt thereof, but not treating a patient having severe renalimpairment or kidney failure with ertugliflozin or a co-crystal or apharmaceutically acceptable salt thereof.

In one embodiment, the method further comprises treating a patienthaving mild renal impairment or normal renal function with ertugliflozinor a co-crystal or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention further provides a methodcomprising: a) identifying a patient in need of treatment for type 2diabetes mellitus; b) assessing the renal function of said patient; c)treating a patient having moderate renal impairment with ertugliflozinor a co-crystal or a pharmaceutically acceptable salt thereof, but nottreating a patient having severe renal impairment or kidney failure withertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof.

In one embodiment, the method further comprises treating a patienthaving mild renal impairment or normal renal function with ertugliflozinor a co-crystal or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention further provides a method oftreating prediabetes, type 1 or type 2 diabetes mellitus or improvingglycemic control in a patient with prediabetes, type 1 or type 2diabetes mellitus, said method comprising: a) assessing the renalfunction of said patient; b) treating a patient having moderate A renalimpairment with ertugliflozin or a co-crystal or a pharmaceuticallyacceptable salt thereof, but not treating a patient having moderate Brenal impairment, severe renal impairment or kidney failure withertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof.

In one embodiment, the method further comprises treating a patienthaving mild renal impairment or normal renal function with ertugliflozinor a co-crystal or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention further provides a methodcomprising: a) identifying a patient in need of treatment for type 2diabetes mellitus; b) assessing the renal function of said patient; c)treating a patient having moderate A renal impairment with ertugliflozinor a co-crystal or a pharmaceutically acceptable salt thereof, but nottreating a patient having moderate B renal impairment, severe renalimpairment or kidney failure with ertugliflozin or a co-crystal or apharmaceutically acceptable salt thereof.

In one embodiment, the method further comprises treating a patienthaving mild renal impairment or normal renal function with ertugliflozinor a co-crystal or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention further provides a method oftreating type 2 diabetes comprising: a) determining the eGFR of apatient in need of treatment for prediabetes, type 1 or type 2 diabetesmellitus; b) administering ertugliflozin or a co-crystal or apharmaceutically acceptable salt thereof to the patient, if the eGFR ofthe patient is ≥30 ml/min/1.73 m².

In one embodiment, ertugliflozin or a co-crystal or a pharmaceuticallyacceptable salt thereof is administered if the eGFR of the patient isbetween ≥30 ml/min/1.73 m² and <60 ml/min/1.73 m². In one embodiment,the method further comprises discontinuing ertugliflozin or a co-crystalor a pharmaceutically acceptable salt thereof if the eGFR of the patientfalls below 30 ml/min/1.73 m². In one embodiment, ertugliflozin or aco-crystal or a pharmaceutically acceptable salt thereof is administeredif the eGFR of the patient is between ≥45 ml/min/1.73 m² and <60ml/min/1.73 m². In one embodiment, the method further comprisesdiscontinuing ertugliflozin or a co-crystal or a pharmaceuticallyacceptable salt thereof if the eGFR of the patient falls below 45ml/min/1.73 m².

In one embodiment, the present invention further provides a methodcomprising: a) assessing the renal function of a patient; b)administering ertugliflozin or a co-crystal or a pharmaceuticallyacceptable salt thereof to the patient; c) discontinuing ertugliflozinor a co-crystal or a pharmaceutically acceptable salt thereof if theeGFR of the patient falls below 30 ml/min/1.73 m².

In one embodiment, ertugliflozin or a co-crystal or a pharmaceuticallyacceptable salt thereof is administered if the eGFR of the patient isbetween ≥30 ml/min/1.73 m² and <60 ml/min/1.73 m².

In one embodiment, the present invention further provides a methodcomprising: a) assessing the renal function of a patient; b)administering ertugliflozin or a co-crystal or a pharmaceuticallyacceptable salt thereof to the patient; c) discontinuing ertugliflozinor a co-crystal or a pharmaceutically acceptable salt thereof if theeGFR of the patient falls below 45 ml/min/1.73 m².

In one embodiment, ertugliflozin or a co-crystal or a pharmaceuticallyacceptable salt thereof is administered if the eGFR of the patient isbetween ≥45 ml/min/1.73 m² and <60 ml/min/1.73 m².

In one embodiment, the present invention further provides a method oftreating prediabetes, type 1 or type 2 diabetes mellitus comprising: a)determining that the eGFR of a patient in need of treatment for type 2diabetes mellitus is between 30 ml/min/1.73 m² and <60 ml/min/1.73 m²;b) administering ertugliflozin or a co-crystal or a pharmaceuticallyacceptable salt thereof to the patient.

In one embodiment, the method further comprises discontinuingertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof if the eGFR of the patient falls below 30 ml/min/1.73 m².

In one embodiment, the present invention further provides a method oftreating prediabetes, type 1 or type 2 diabetes mellitus comprising: a)determining that the eGFR of a patient in need of treatment for type 2diabetes mellitus is between ≥45 ml/min/1.73 m² and <60 ml/min/1.73 m²;b) administering ertugliflozin or a co-crystal or a pharmaceuticallyacceptable salt thereof to the patient.

In one embodiment, the method further comprises discontinuingertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof if the eGFR of the patient falls below 45 ml/min/1.73 m².

In one embodiment, the present invention further provides a method oftreating prediabetes, type 1 or type 2 diabetes mellitus in a patienthaving an eGFR between 30 ml/min/1.73 m² and <60 ml/min/1.73 m²comprising: a) measuring the patient's eGFR b) measuring theeffectiveness of ertugliflozin or a co-crystal or a pharmaceuticallyacceptable salt thereof for treatment of prediabetes, type 1 or type 2diabetes mellitus in said patients; and c) administering ertugliflozinor a co-crystal or a pharmaceutically acceptable salt thereof to thepatient.

In one embodiment, the patient has an eGFR between ≥45 ml/min/1.73 m²and <60 ml/min/1.73 m². The effectiveness of ertugliflozin is forexample measured by determining the % HbA1c of the free plasma glucose(FPG) in the patient.

In one embodiment, the present invention further provides a method oftreatment comprising: a) identifying a patient as being in need oftreatment for prediabetes, type 1 or type 2 diabetes mellitus; b)determining that the patient's eGFR is ≥30 ml/min/1.73 m²; c) selectinga prediabetes, type 1 or type 2 diabetes mellitus treatment for thepatient that comprises the administration of ertugliflozin or aco-crystal or a pharmaceutically acceptable salt thereof, based on therecognition that ertugliflozin is effective for treatment of type 2diabetes mellitus in patients whose eGFR is ≥30 ml/min/1.73 m² and notin patients whose eGFR is <30 ml/min/1.73 m²; and d) administeringertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof to the patient.

In one embodiment, step b) comprises determining that the patient's eGFRis ≥30 ml/min/1.73 m² and <90 ml/min/1.73 m². In one embodiment, step b)comprises determining that the patient's eGFR is ≥30 ml/min/1.73 m² and<60 ml/min/1.73 m².

In one embodiment, the present invention further provides a method oftreatment comprising: a) identifying a patient with prediabetes, type 1or type 2 diabetes mellitus in need of improvement of glycemic control;b) determining that the patient's eGFR is ≥30 ml/min/1.73 m²; c)selecting a prediabetes, type 1 or type 2 diabetes mellitus treatmentfor the patient that comprises the administration of ertugliflozin or aco-crystal or a pharmaceutically acceptable salt thereof, based on therecognition that ertugliflozin is effective for treatment ofprediabetes, type 1 or type 2 diabetes mellitus in patients whose eGFRis ≥30 ml/min/1.73 m² and not in patients whose eGFR is <30 ml/min/1.73m²; and d) administering ertugliflozin or a co-crystal or apharmaceutically acceptable salt thereof to the patient.

In one embodiment, step b) comprises determining that the patient'sestimated glomerular filtration rate (eGFR) is ≥30 ml/min/1.73 m² and<90 ml/min/1.73 m². In one embodiment, step b) comprises determiningthat the patient's eGFR is ≥30 ml/min/1.73 m² and <60 ml/min/1.73 m² .

In one embodiment, the present invention further provides a method oftreatment comprising: a) identifying a patient as being in need oftreatment for prediabetes, type 1 or type 2 diabetes mellitus; b)measuring the patient's eGFR; c) determining that the patient's eGFR is≥30 ml/min/1.73 m² and <60 ml/min/1.73 m² d) prescribing a prediabetes,type 1 or type 2 diabetes mellitus treatment for the patient thatincludes use of ertugliflozin or a co-crystal or a pharmaceuticallyacceptable salt thereof, based on the recognition that ertugliflozin iseffective for treatment of type 2 diabetes in patients whose eGFR is ≥30ml/min/1.73 m² and not in patients whose eGFR is <30 ml/min/1.73 m²; ande) administering ertugliflozin or a co-crystal or a pharmaceuticallyacceptable salt thereof to the patient.

In one embodiment, the present invention further provides a method oftreatment comprising: a) identifying a patient as being in need oftreatment for prediabetes, type 1 or type 2 diabetes mellitus; b)determining that the patient's eGFR is ≥30 ml/min/1.73 m² and <60ml/min/1.73 m²; c) selecting ertugliflozin as a treatment for thepatient based on the recognition that ertugliflozin is effective fortreatment of type 2 diabetes mellitus in patients who have an eGFR of 30ml/min/1.73 m² but may lack efficacy in patients with eGFR <30ml/min/1.73 m²; d) administering a pharmaceutical composition comprisingertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof to the patient; e) determining during treatment with thepharmaceutical composition that the patient's eGFR has dropped below 30ml/min/1.73 m²; and f) ceasing treatment of the patient with thepharmaceutical composition, based on the recognition that ertugliflozinmay lack efficacy in patients with eGFR <30 ml/min/1.73 m².

In one embodiment, the present invention further provides a method oftreatment comprising: a) identifying a patient as being in need oftreatment for prediabetes, type 1 or type 2 diabetes mellitus; b)measuring the patient's eGFR; c) determining that the patient's eGFR is≥30 ml/min/1.73 m² and <60 ml/min/1.73 m². d) prescribing a type 2diabetes treatment for the patient that includes use of ertugliflozin,based on the recognition that ertugliflozin is effective for treatmentof type 2 diabetes in patients whose eGFR is ≥30 ml/min/1.73 m² and notin patients whose eGFR is <30 ml/min/1.73 m²; and e) advising thepatient to self-administer ertugliflozin or a co-crystal or apharmaceutically acceptable salt thereof.

In one embodiment, the present invention further provides a method oftreatment comprising: a) identifying a patient as being in need oftreatment for prediabetes, type 1 or type 2 diabetes mellitus; b)treating the patient with a first treatment regimen that does notcomprise use of ertugliflozin or a co-crystal or a pharmaceuticallyacceptable salt thereof; c) determining that the first treatment regimendoes not provide adequate glycemic control in the patient; d) measuringthe patient's eGFR; e) determining that the patient's eGFR is ≥30ml/min/1.73 m² and <60 ml/min/1.73 m²; f) prescribing an alteredtreatment regimen for the patient that includes use of ertugliflozin,based on the recognition that ertugliflozin is effective for treatmentof prediabetes, type 1 or type 2 diabetes mellitus in patients whoseeGFR is ≥30 ml/min/1.73 m² and not in patients whose eGFR is <30ml/min/1.73 m²; g) advising the patient to administer ertugliflozin or aco-crystal or a pharmaceutically acceptable salt thereof daily as partof the altered treatment regimen; and h) confirming that the patient'sglycemic control is improved on the altered treatment regimen, comparedto on the first treatment regimen.

In one embodiment, the present invention further provides a method oftreatment comprising: a) identifying a patient as being in need oftreatment for prediabetes, type 1 or type 2 diabetes mellitus; b)determining that the patient's eGFR is ≥45 ml/min/1.73 m² and <60ml/min/1.73 m²; c) selecting a type 2 diabetes treatment for the patientthat includes ertugliflozin, based on the recognition that ertugliflozinis effective for treatment of prediabetes, type 1 or type 2 diabetesmellitus in patients whose eGFR is ≥45 ml/min/1.73 m² and not inpatients whose eGFR is ≤45 ml/min/1.73 m²; and d) administeringertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof to the patient.

In one embodiment, the present invention further provides a method oftreatment comprising: a) identifying a patient as being in need oftreatment for prediabetes, type 1 or type 2 diabetes mellitus; b)measuring the patient's eGFR; c) determining that the patient's eGFR is≥45 ml/min/1.73 m² and <60 ml/min/1.73 m². d) prescribing a prediabetes,type 1 or type 2 diabetes mellitus treatment for the patient thatincludes use of ertugliflozin, based on the recognition thatertugliflozin is effective for treatment of type 2 diabetes mellitus inpatients whose eGFR is ≥45 ml/min/1.73 m² and not in patients whose eGFRis ≤45 ml/min/1.73 m²; and e) administering ertugliflozin or aco-crystal or a pharmaceutically acceptable salt thereof to the patient.

In one embodiment, the present invention further provides a method oftreatment comprising: a) identifying a patient as being in need oftreatment for prediabetes, type 1 or type 2 diabetes mellitus; b)determining that the patient's eGFR is ≥45 ml/min/1.73 m² and <60ml/min/1.73 m². c) selecting ertugliflozin as a treatment for thepatient based on the recognition that ertugliflozin is effective fortreatment of prediabetes, type 1 or type 2 diabetes mellitus in patientswho have an eGFR of ≥45 ml/min/1.73 m² but may lack efficacy in patientswith eGFR ≤45 ml/min/1.73 m²; d) administering a pharmaceuticalcomposition comprising ertugliflozin or a co-crystal or apharmaceutically acceptable salt thereof to the patient; e) determiningduring treatment with the pharmaceutical composition that the patient'seGFR has dropped below 45 ml/min/1.73 m²; and f) ceasing treatment ofthe patient with the pharmaceutical composition, based on therecognition that ertugliflozin may lack efficacy in patients with eGFR≤45 ml/min/1.73 m².

In one embodiment, the present invention further provides a method oftreatment comprising: a) identifying a patient as being in need oftreatment for prediabetes, type 1 or type 2 diabetes mellitus; b)measuring the patient's eGFR; c) determining that the patient's eGFR is≥45 ml/min/1.73 m² and <60 ml/min/1.73 m². d) prescribing a type 2diabetes treatment for the patient that includes use of ertugliflozin,based on the recognition that ertugliflozin is effective for treatmentof prediabetes, type 1 or type 2 diabetes mellitus in patients whoseeGFR is ≥45 ml/min/1.73 m² and not in patients whose eGFR is ≤45ml/min/1.73 m²; and e) advising the patient to self-administerertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof.

In one embodiment, the present invention further provides a method oftreatment comprising: a) identifying a patient as being in need oftreatment for prediabetes, type 1 or type 2 diabetes mellitus; b)treating the patient with a first treatment regimen that does notcomprise use of ertugliflozin; c) determining that the first treatmentregimen does not provide adequate glycemic control in the patient; d)measuring the patient's eGFR; e) determining that the patient's eGFR is≥45 ml/min/1.73 m² and <60 ml/min/1.73 m² f) prescribing an alteredtreatment regimen for the patient that includes use of ertugliflozin,based on the recognition that ertugliflozin is effective for treatmentof prediabetes, type 1 or type 2 diabetes mellitus in patients whoseeGFR is ≥45 ml/min/1.73 m² and not in patients whose eGFR is ≤45ml/min/1.73 m²; g) advising the patient to administer ertugliflozin or aco-crystal or a pharmaceutically acceptable salt thereof daily as partof the altered treatment regimen; and h) confirming that the patient'sglycemic control is improved on the altered treatment regimen, comparedto on the first treatment regimen.

In one embodiment, in any one of the methods above ertugliflozin or aco-crystal or a pharmaceutically acceptable salt thereof is administeredas a pharmaceutical composition, for example a tablet. In oneembodiment, the pharmaceutical composition comprises 5 mg or 15 mg ofertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof. In one embodiment, ertugliflozin is administered once daily.

In one embodiment, the present invention further provides a method ofimprovement of glycemic control in a patient with prediabetes, type 1 ortype 2 diabetes mellitus, wherein the patient's eGFR is ≥30 ml/min/1.73m² comprising the administration of a pharmaceutical compositioncomprising ertugliflozin or a co-crystal or a pharmaceuticallyacceptable salt thereof to the patient. In one embodiment, the patient'seGFR is ≥45 ml/min/1.73 m². In one embodiment, the present inventionfurther provides a method of improvement of glycemic control in a type 2diabetes mellitus patient with moderate renal impairment comprising theadministration of a pharmaceutical composition comprising ertugliflozinor a co-crystal or a pharmaceutically acceptable salt thereof to thepatient. In one embodiment, the patient is with moderate A renal (CKDstage 3A) impairment. In one embodiment, the patient is with moderate Brenal (CKD stage 3B) impairment. In one embodiment, the pharmaceuticalcomposition comprises 5 mg or 15 mg of ertugliflozin or a co-crystal ora pharmaceutically acceptable salt thereof. In one embodiment,ertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof is administered once daily.

In one embodiment, the present invention further provides ertugliflozinor a co-crystal or a pharmaceutically acceptable salt thereof for use inthe treatment of prediabetes, type 1 or type 2 diabetes mellitus in apatient wherein the patient's eGFR is ≥30 ml/min/1.73 m².

In one embodiment, the present invention further provides apharmaceutical composition comprising ertugliflozin or a co-crystal or apharmaceutically acceptable salt thereof for use in the treatment ofprediabetes, type 1 or type 2 diabetes mellitus in a patient wherein thepatient's eGFR is ≥30 ml/min/1.73 m².

In one embodiment, the present invention further provides ertugliflozinor a co-crystal or a pharmaceutically acceptable salt thereof for use inthe improvement of glycemic control in a patient with prediabetes, type1 or type 2 diabetes mellitus wherein the patient's estimated glomerularfiltration rate (eGFR) is ≥30 ml/min/1.73 m².

In one embodiment, the present invention further provides apharmaceutical composition comprising ertugliflozin or a co-crystal or apharmaceutically acceptable salt thereof for use in the improvement ofglycemic control in a patient with prediabetes, type 1 or type 2diabetes mellitus wherein the patient's eGFR is ≥30 ml/min/1.73 m².

In one embodiment, in any of the use of ertugliflozin or a co-crystal ora pharmaceutically acceptable salt thereof or a pharmaceuticalcomposition above, the patient's eGFR is ≥30 ml/min/1.73 m² and <90ml/min/1.73 m². In one embodiment, the patient's eGFR is ≥30 ml/min/1.73m² and <60 ml/min/1.73 m². In one embodiment, the patient's eGFR is ≥45ml/min/1.73 m². In one embodiment, the patient's eGFR is ≥45 ml/min/1.73m² and <90 ml/min/1.73 m². In one embodiment, the patient's eGFR is ≥45ml/min/1.73 m² and <60 ml/min/1.73 m².

In one embodiment, the present invention further provides ertugliflozinor a co-crystal or a pharmaceutically acceptable salt thereof for use inthe treatment of prediabetes, type 1 or type 2 diabetes mellitus in apatient with moderate renal impairment. In one embodiment, the presentinvention provides a pharmaceutical composition comprising ertugliflozinor a co-crystal or a pharmaceutically acceptable salt thereof for use inthe treatment of prediabetes, type 1 or type 2 diabetes mellitus in apatient with moderate renal impairment. In one embodiment, the presentinvention provides ertugliflozin or a co-crystal or a pharmaceuticallyacceptable salt thereof for use in the improvement of glycemic controlin a prediabetes, type 1 or type 2 diabetes mellitus patient withmoderate renal impairment. In one embodiment, the present inventionprovides a pharmaceutical composition comprising ertugliflozin or aco-crystal or a pharmaceutically acceptable salt thereof for use in theimprovement of glycemic control in a prediabetes, type 1 or type 2diabetes mellitus patient with moderate renal impairment.

In one embodiment, in any use of ertugliflozin or a co-crystal or apharmaceutically acceptable salt thereof or a pharmaceutical compositionabove, the patient is with moderate A renal impairment or with moderateB renal impairment. In one embodiment, the use is as an adjunct to dietand exercise. In one embodiment, the patient is an adult patient. In oneembodiment, the use is once daily. In one embodiment, the use is 5 mg or15 mg once daily.

In one aspect of the present invention, in a method or use disclosedherein a patient is patient with type 2 diabetes mellitus (or type 2diabetes mellitus patient), a patient treated for type 2 diabetesmellitus, a patient diagnosed with type 2 diabetes mellitus or a patientin need of treatment for type 2 diabetes mellitus. In one aspect, apatient is a patient with pre-diabetes.

In a further aspect, the present invention provides a method ofimproving glycemic control in a patient with type 2 diabetes mellitus,said method comprising a) administering to a patient 5 mg ofertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof daily, b) determining that the patient requires additionalglycemic control and c) administering to the patient 15 mg ofertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof daily.

In a further aspect of the present invention, in a method or usedescribed herein ertugliflozin or a co-crystal or a pharmaceuticallyacceptable salt thereof is administered to a patient at a starting doseof 5 mg daily, for example to a patient having an eGFR ≥30 ml/min/1.73m² or to a patient having an eGFR ≥45 ml/min/1.73 m². In one aspect, insaid method or use, the dose is increased to 15 mg daily, for example ifthe patient requires additional glycemic control. In one aspect, thedose of ertugliflozin or a co-crystal or a pharmaceutically acceptablesalt thereof is increased to 15 mg daily in a patient having an eGFR ≥30ml/min/1.73 m², in a patient having an eGFR ≥45 ml/min/1.73 m² or in apatient having an eGFR ≥60 ml/min/1.73 m².

In a further aspect, the present invention provides a method ofimproving glycemic control in a patient with type 2 diabetes mellitus,said method comprising a) administering 5 mg of ertugliflozin or aco-crystal or a pharmaceutically acceptable salt thereof daily to apatient having an eGFR ≥30 ml/min/1.73 m² and b) increasing the dose ofertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof administered to the patient to 15 mg daily in a patient havingan eGFR ≥30 ml/min/1.73 m². In one aspect, said patient in step a)requires additional glycemic control.

In a further aspect, the present invention provides a method ofimproving glycemic control in a patient with type 2 diabetes mellitus,said method comprising a) administering 5 mg of ertugliflozin or aco-crystal or a pharmaceutically acceptable salt thereof daily to apatient having an eGFR ≥30 ml/min/1.73 m², b) determining that thepatient has an eGFR ≥30 ml/min/1.73 m² and c) administering 15 mg ofertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof daily to the patient. In one aspect, step b) further comprisesdetermining that the patient requires additional glycemic control.

In a further aspect, the present invention provides a method ofimproving glycemic control in a patient with type 2 diabetes mellitus,said method comprising a) administering 5 mg of ertugliflozin or aco-crystal or a pharmaceutically acceptable salt thereof daily to apatient having an eGFR ≥30 ml/min/1.73 m² and b) increasing the dose ofertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof administered to the patient to 15 mg daily in a patient havingan eGFR ≥45 ml/min/1.73 m². In one aspect, said patient in step a)requires additional glycemic control.

In a further aspect, the present invention provides a method ofimproving glycemic control in a patient with type 2 diabetes mellitus,said method comprising a) administering 5 mg of ertugliflozin or aco-crystal or a pharmaceutically acceptable salt thereof daily to apatient having an eGFR ≥30 ml/min/1.73 m², b) determining that thepatient has an eGFR ≥45 ml/min/1.73 m² and c) administering 15 mg ofertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof daily to the patient. In one aspect, step b) further comprisesdetermining that the patient requires additional glycemic control.

In a further aspect, the present invention provides a method ofimproving glycemic control in a patient with type 2 diabetes mellitus,said method comprising a) administering 5 mg of ertugliflozin or aco-crystal or a pharmaceutically acceptable salt thereof daily to apatient having an eGFR ≥30 ml/min/1.73 m² and b) increasing the dose ofertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof administered to the patient to 15 mg daily in a patient havingan eGFR ≥60 ml/min/1.73 m². In one aspect, said patient in step a)requires additional glycemic control.

In a further aspect, the present invention provides a method ofimproving glycemic control in a patient with type 2 diabetes mellitus,said method comprising a) administering 5 mg of ertugliflozin or aco-crystal or a pharmaceutically acceptable salt thereof daily to apatient having an eGFR ≥30 ml/min/1.73 m², b) determining that thepatient has an eGFR ≥60 ml/min/1.73 m² and c) administering 15 mg ofertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof daily to the patient. In one aspect, step b) further comprisesdetermining that the patient requires additional glycemic control.

In a further aspect, the present invention provides a method ofimproving glycemic control in a patient with type 2 diabetes mellitus,said method comprising a) administering 5 mg of ertugliflozin or aco-crystal or a pharmaceutically acceptable salt thereof daily to apatient having an eGFR ≥45 ml/min/1.73 m² and b) increasing the dose ofertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof administered to the patient to 25 mg daily in a patient havingan eGFR ≥45 ml/min/1.73 m². In one aspect, said patient in step a)requires additional glycemic control.

In a further aspect, the present invention provides a method ofimproving glycemic control in a patient with type 2 diabetes mellitus,said method comprising a) administering 5 mg of ertugliflozin or aco-crystal or a pharmaceutically acceptable salt thereof daily to apatient having an eGFR ≥45 ml/min/1.73 m², b) determining that thepatient has an eGFR ≥45 ml/min/1.73 m² and c) administering 15 mg ofertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof daily to the patient. In one aspect, step b) further comprisesdetermining that the patient requires additional glycemic control.

In a further aspect, the present invention provides a method ofimproving glycemic control in a patient with type 2 diabetes mellitus,said method comprising a) administering 5 mg of ertugliflozin or aco-crystal or a pharmaceutically acceptable salt thereof daily to apatient having an eGFR ≥45 ml/min/1.73 m² and b) increasing the dose ofertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof administered to the patient to 15 mg daily in a patient havingan eGFR ≥60 ml/min/1.73 m². In one aspect, said patient in step a)requires additional glycemic control.

In a further aspect, the present invention provides a method ofimproving glycemic control in a patient with type 2 diabetes mellitus,said method comprising a) administering 5 mg of ertugliflozin or aco-crystal or a pharmaceutically acceptable salt thereof daily to apatient having an eGFR ≥45 ml/min/1.73 m², b) determining that thepatient has an eGFR ≥60 ml/min/1.73 m² and c) administering 15 mg ofertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof daily to the patient. In one aspect, step b) further comprisesdetermining that the patient requires additional glycemic control.

In a further embodiment, in a method or use described hereinertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof is administered to a patient at a dose of 5 mg daily to apatient having an eGFR ≥60 ml/min/1.73 m² and the patient continues tobe administered ertugliflozin or a co-crystal or a pharmaceuticallyacceptable salt thereof at a dose of 5 mg daily if the patient's eGFR isreduced to 30 to ≤60 ml/min/1.73 m² or to ≥45 to <60 ml/min/1.73 m².Accordingly, in one aspect, the present invention provides a method ofimproving glycemic control in a patient with type 2 diabetes mellitus,said method comprising a) administering 5 mg of ertugliflozin or aco-crystal or a pharmaceutically acceptable salt thereof daily to apatient having an eGFR ≥60 ml/min/1.73 m², b) determining that thepatient has an eGFR ≥30 to <60 ml/min/1.73 m² and c) continuing toadminister 5 mg of ertugliflozin or a co-crystal or a pharmaceuticallyacceptable salt thereof daily to the patient. In an another aspect, thepresent invention provides a method of improving glycemic control in apatient with type 2 diabetes mellitus, said method comprising a)administering 5 mg of ertugliflozin or a co-crystal or apharmaceutically acceptable salt thereof daily to a patient having aneGFR ≥60 ml/min/1.73 m², b) determining that the patient has an eGFR>45to <60 ml/min/1.73 m² and c) continuing to administer 5 mg ofertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof daily to the patient.

In a further embodiment, in a method or use described hereinertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof is administered to a patient at a starting dose of 5 mg daily toa patient having an eGFR ≥60 ml/min/1.73 m², the dose of ertugliflozinor a co-crystal or a pharmaceutically acceptable salt thereof isincreased to 15 mg daily, for example if the patient requires additionalglycemic control, and the dose of ertugliflozin or a co-crystal or apharmaceutically acceptable salt thereof administered to the patientstays at a dose of 15 mg daily if the patient's eGFR is reduced to 30 to≤60 ml/min/1.73 m² or to 45 to ≤60 ml/min/1.73 m². Accordingly, in oneaspect, the present invention provides a method of improving glycemiccontrol in a patient with type 2 diabetes mellitus, said methodcomprising a) administering 5 mg of ertugliflozin or a co-crystal or apharmaceutically acceptable salt thereof daily to a patient having aneGFR ≥60 ml/min/1.73 m², b) increasing the dose of ertugliflozin or aco-crystal or a pharmaceutically acceptable salt thereof administered tothe patient to 15 mg daily, for example if the patient requiresadditional glycemic control, c) determining that the patient has an eGFR≥30 to <60 ml/min/1.73 m² and d) administering 15 mg of ertugliflozin ora co-crystal or a pharmaceutically acceptable salt thereof daily to thepatient. In a further aspect, the present invention provides a method ofimproving glycemic control in a patient with type 2 diabetes mellitus,said method comprising a) administering 5 mg of ertugliflozin or aco-crystal or a pharmaceutically acceptable salt thereof daily to apatient having an eGFR ≥60 ml/min/1.73 m², b) increasing the dose ofertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof administered to the patient to 15 mg daily, for example if thepatient requires additional glycemic control, c) determining that thepatient has an eGFR ≥45 to <60 ml/min/1.73 m² and d) administering 15 mgertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof daily to the patient.

In a further embodiment, in a method or use described hereinertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof is administered to a patient at a starting dose of 5 mg daily toa patient having an eGFR ≥60 ml/min/1.73 m², the dose of ertugliflozinor a co-crystal or a pharmaceutically acceptable salt thereof isincreased to 15 mg daily, for example if the patient requires additionalglycemic control, and the dose of ertugliflozin or a co-crystal or apharmaceutically acceptable salt thereof administered to the patient isreduced to a dose of 5 mg daily if the patient's eGFR is reduced to 30to <60 ml/min/1.73 m² or to ≥45 to <60 ml/min/1.73 m². Accordingly, inone aspect, the present invention provides a method of improvingglycemic control in a patient with type 2 diabetes mellitus, said methodcomprising a) administering 5 mg of ertugliflozin or a co-crystal or apharmaceutically acceptable salt thereof daily to a patient having aneGFR ≥60 ml/min/1.73 m², b) increasing the dose of ertugliflozin or aco-crystal or a pharmaceutically acceptable salt thereof administered tothe patient to 15 mg daily, for example if the patient requiresadditional glycemic control, c) determining that the patient has an eGFR≥30 to <60 ml/min/1.73 m² and d) administering 5 mg of ertugliflozin ora co-crystal or a pharmaceutically acceptable salt thereof daily to thepatient. In a further aspect, the present invention provides a method ofimproving glycemic control in a patient with type 2 diabetes mellitus,said method comprising a) administering 5 mg of ertugliflozin or aco-crystal or a pharmaceutically acceptable salt thereof daily to apatient having an eGFR ≥60 ml/min/1.73 m², b) increasing the dose ofertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof administered to the patient to 15 mg daily, for example if thepatient requires additional glycemic control, c) determining that thepatient has an eGFR ≥45 to <60 ml/min/1.73 m² and d) administering 10 mgof ertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof daily to the patient.

In a further embodiment, in a method or use described hereinertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof is administered to a patient to lower urinary albumin excretionin the patient, wherein the patient has moderate renal impairment orstage 3 chronic kidney disease (CKD).

In a further embodiment, in a method or use described hereinertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof is administered to a patient who has suffered an ischemic stroketo reduce neuronal damage caused by hyperglycemia following the ischemicstroke.

In a further embodiment, in a method or use described hereinertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof is administered to a patient who has suffered traumatic braininjury to reduce neuronal damage caused by hyperglycemia following thebrain injury.

In a further embodiment, in a method or use described hereinertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof is administered to a patient who has suffered a closed-headtraumatic brain injury to reduce neuronal damage caused by hyperglycemiafollowing the brain injury.

In one aspect, in any one of the methods of uses described above,ertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof is administered once daily to a patient, i.e. for example 5 mgor 15 mg of ertugliflozin or a co-crystal or a pharmaceuticallyacceptable salt thereof is administered once daily to a patient.

Another embodiment of the present invention is a pharmaceuticalcomposition for use in the methods described herein comprising atherapeutically effective amount of a compound described herein and apharmaceutically acceptable excipient, diluent or carrier. The compoundsdescribed herein (including the compositions and processes used therein)may also be used in the manufacture of a medicament for the therapeuticapplications described herein.

A typical formulation is prepared by mixing a compound of the presentinvention and a carrier, diluent or excipient. Suitable carriers,diluents and excipients are well known to those skilled in the art andinclude materials such as carbohydrates, waxes, water soluble and/orswellable polymers, hydrophilic or hydrophobic materials, gelatin, oils,solvents, water, and the like. The particular carrier, diluent orexcipient used will depend upon the means and purpose for which thecompound of the present invention is being applied. Solvents aregenerally selected based on solvents recognized by persons skilled inthe art as safe (GRAS) to be administered to a mammal. In general, safesolvents are non-toxic aqueous solvents such as water and othernon-toxic solvents that are soluble or miscible in water. Suitableaqueous solvents include water, ethanol, propylene glycol, polyethyleneglycols (e.g., PEG400, PEG300), etc. and mixtures thereof. Theformulations may also include one or more buffers, stabilizing agents,surfactants, wetting agents, lubricating agents, emulsifiers, suspendingagents, preservatives, antioxidants, opaquing agents, glidants,processing aids, colorants, sweeteners, perfuming agents, flavoringagents and other known additives to provide an elegant presentation ofthe drug (i.e., a compound of the present invention or pharmaceuticalcomposition thereof) or aid in the manufacturing of the pharmaceuticalproduct (i.e., medicament).

The formulations may be prepared using conventional dissolution andmixing procedures. For example, the bulk drug substance (i.e., compoundof the present invention or stabilized form of the compound (e.g.,complex with a cyclodextrin derivative or other known complexationagent)) is dissolved in a suitable solvent in the presence of one ormore of the excipients described above. The compound of the presentinvention is typically formulated into pharmaceutical dosage forms toprovide an easily controllable dosage of the drug and to give thepatient an elegant and easily handleable product.

The pharmaceutical compositions also include solvates and hydrates ofthe compounds of Formula (A) or Formula (B). The term “solvate” refersto a molecular complex of a compound represented by Formula (A) orFormula (B) (including pharmaceutically acceptable salts thereof) withone or more solvent molecules. Such solvent molecules are those commonlyused in the pharmaceutical art, which are known to be innocuous to therecipient, e.g., water, ethanol, ethylene glycol, and the like, The term“hydrate” refers to the complex where the solvent molecule is water. Thesolvates and/or hydrates preferably exist in crystalline form. Othersolvents may be used as intermediate solvates in the preparation of moredesirable solvates, such as methanol, methyl t-butyl ether, ethylacetate, methyl acetate, (S)-propylene glycol, (R)-propylene glycol,1,4-butyne-diol, and the like. The crystalline forms may also exist ascomplexes with other innocuous small molecules, such as L-phenylalanine,L-proline, L-pyroglutamic acid and the like, as co-crystals or solvatesor hydrates of the co-crystalline material. The solvates, hydrates andco-crystalline compounds may be prepared using procedures described inPCT Publication No. WO 08/002824, incorporated herein by reference, orother procedures well-known to those of skill in the art.

The pharmaceutical composition (or formulation) for application may bepackaged in a variety of ways depending upon the method used foradministering the drug. Generally, an article for distribution includesa container having deposited therein the pharmaceutical formulation inan appropriate form. Suitable containers are well-known to those skilledin the art and include materials such as bottles (plastic and glass),sachets, ampoules, plastic bags, metal cylinders, and the like. Thecontainer may also include a tamper-proof assemblage to preventindiscreet access to the contents of the package. In addition, thecontainer has deposited thereon a label that describes the contents ofthe container. The label may also include appropriate warnings.

The compounds of this invention may also be used in conjunction withother pharmaceutical agents for the treatment of the diseases,conditions and/or disorders described herein. Therefore, methods oftreatment that include administering compounds of the present inventionin combination with other pharmaceutical agents are also provided.Suitable pharmaceutical agents that may be used in combination with thecompounds of the present invention include anti-obesity agents(including appetite suppressants), anti-diabetic agents,anti-hyperglycemic agents, lipid lowering agents, anti-inflammatoryagents and anti-hypertensive agents.

Suitable anti-obesity agents include cannabinoid-1 (CB-1) antagonists(such as rimonabant), 11β-hydroxy steroid dehydrogenase-1 (11β-HSDtype 1) inhibitors, stearoyl-CoA desaturase-1 (SCD-1) inhibitor, MCR-4agonists, cholecystokinin-A (CCK-A) agonists, monoamine reuptakeinhibitors (such as sibutramine), sympathomimetic agents, β₃ adrenergicagonists, dopamine agonists (such as bromocriptine),melanocyte-stimulating hormone analogs, 5HT2c agonists, melaninconcentrating hormone antagonists, leptin (the OB protein), leptinanalogs, leptin agonists, galanin antagonists, lipase inhibitors (suchas tetrahydrolipstatin, i.e. orlistat), anorectic agents (such as abombesin agonist), neuropeptide-Y antagonists (e.g., NPY Y5antagonists), PYY₃₋₃₆ (including analogs thereof), thyromimetic agents,dehydroepiandrosterone or an analog thereof, glucocorticoid agonists orantagonists, orexin antagonists, glucagon-like peptide-1 agonists,ciliary neurotrophic factors (such as Axokine™ available from RegeneronPharmaceuticals, Inc., Tarrytown, N.Y. and Procter & Gamble Company,Cincinnati, Ohio), human agouti-related protein (AGRP) inhibitors,ghrelin antagonists, histamine 3 antagonists or inverse agonists,neuromedin U agonists, MTP/ApoB inhibitors (e.g., gut-selective MTPinhibitors, such as dirlotapide), opioid antagonist, orexin antagonist,and the like.

Preferred anti-obesity agents for use in the combination aspects of thepresent invention include CB-1 antagonists (e.g., rimonabant,taranabant, surinabant, otenabant, SLV319 (CAS No. 464213-10-3) andAVE1625 (CAS No. 358970-97-5)), gut-selective MTP inhibitors (e.g.,dirlotapide, mitratapide and implitapide, R56918 (CAS No. 403987) andCAS No. 913541-47-6), CCKa agonists (e.g.,N-benzyl-2-[4-(1H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-acetamidedescribed in PCT Publication No. WO 2005/116034 or US Publication No.2005-0267100 A1), 5HT2c agonists (e.g., lorcaserin), MCR4 agonist (e.g.,compounds described in U.S. Pat. No. 6,818,658), lipase inhibitor (e.g.,Cetilistat), PYY₃₋₃₆(as used herein “PYY₃₋₃₆” includes analogs, such aspeglated PYY₃₋₃₆ e.g., those described in US Publication 2006/0178501),opioid antagonists (e.g., naltrexone), oleoyl-estrone (CAS No.180003-17-2), obinepitide (TM30338), pramlintide (Symlin®), tesofensine(NS2330), leptin, liraglutide, bromocriptine, orlistat, exenatide(Byetta®), AOD-9604 (CAS No. 221231-10-3) and sibutramine. Preferably,compounds of the present invention and combination therapies areadministered in conjunction with exercise and a sensible diet.

Suitable anti-diabetic agents include an acetyl-CoA carboxylase-2(ACC-2) inhibitor, a phosphodiesterase (PDE)-10 inhibitor, adiacylglycerol acyltransferase (DGAT) 1 or 2 inhibitor, a sulfonylurea(e.g., acetohexamide, chlorpropamide, diabinese, glibenclamide,glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone,glisolamide, tolazamide, and tolbutamide), a meglitinide, an α-amylaseinhibitor (e.g., tendamistat, trestatin and AL-3688), an α-glucosidehydrolase inhibitor (e.g., acarbose), an α-glucosidase inhibitor (e.g.,adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q,and salbostatin), a PPARγ agonist (e.g., balaglitazone, ciglitazone,darglitazone, englitazone, isaglitazone, pioglitazone, rosiglitazone andtroglitazone), a PPAR α/γ agonist (e.g., CLX-0940, GW-1536, GW-1929,GW-2433, KRP-297, L-796449, LR-90, MK-0767 and SB-219994), a biguanide(e.g., metformin), a glucagon-like peptide 1 (GLP-1) agonist (e.g.,exendin-3 and exendin-4), a protein tyrosine phosphatase-1B (PTP-1B)inhibitor (e.g., trodusquemine, hyrtiosal extract, and compoundsdisclosed by Zhang, S., et al., Drug Discovery Today, 12(9/10), 373-381(2007)), SIRT-1 inhibitor (e.g., reservatrol), a dipeptidyl peptideaseIV (DPP-IV) inhibitor (e.g., sitagliptin, vildagliptin, alogliptin andsaxagliptin), an insulin secreatagogue, a fatty acid oxidationinhibitor, an A2 antagonist, a c-jun amino-terminal kinase (INK)inhibitor, insulin, an insulin mimetic, a glycogen phosphorylaseinhibitor, a VPAC2 receptor agonist and a glucokinase activator.Preferred anti-diabetic agents are metformin and DPP-IV inhibitors(e.g., sitagliptin, vildagliptin, alogliptin and saxagliptin).

In certain embodiments of the methods described herein, ertugliflozin ora co-crystal or a pharmaceutically acceptable salt thereof isadministered in combination with sitagliptin and/or metformin.Ertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof can be administered in the amount of 5 mg or 15 mg whilesitagliptin can be administered in the amount of 25 mg or 50 mg. Ifadministered with metformin, metformin can be administered in the amountof 1000 mg or 2000mg. Such combinations (ertugliflozin and sitagliptinor ertugliflozin and metformin) or triple combinations (ertugliflozin,metformin and sitagliptin) can be administered simultaneously orsequentially. Such combinations and triple combinations can be in asingle pharmaceutical compositions or each pharmaceutical agent can bein a separate pharmaceutical composition.

Suitable anti-inflammatory agents include genital tract/urinary tractinfection preventatives and treatments. Exemplary agents includecranberries (i.e. Vaccinium macrocarpon) and cranberry derivatives suchas cranberry juice, cranberry extracts or flavonols of cranberries.Cranberry extracts may include one or more flavonols (i.e. anthocyaninsand proanthocyanidins) or a purified cranberry flavonol compound,including myricetin-3-β-xylopyranoside, quercetin-3-β-glucoside,quercetin-3-α-arabinopyranoside, 3′-methoxyquercetin-3-α-xylopyranoside,quercetin-3-O-(6″-p-coumaroyl)-β-galactoside,quercetin-3-O-(6″-benzoyl)-β-galactoside, and/orquercetin-3-α-arabinofuranoside.

Embodiments of the present invention are illustrated by the followingExample. It is to be understood, however, that the embodiments of theinvention are not limited to the specific details of the Example, asother variations thereof will be known, or apparent in light of theinstant disclosure, to one of ordinary skill in the art.

EXAMPLES

Results of a Phase I, Single Dose Study to Study The Effect of RenalImpairment on the Pharmacokinetics and Pharmacodynamics of Ertugliflozinin Subjects with Type 2 Diabetes Mellitus (T2DM)

Background and aims: Ertugliflozin is a highly selective and potentinhibitor of Sodium Glucose co-Transporter 2 (SGLT2) that is underdevelopment for the treatment of T2DM. Ertugliflozin inhibits renalglucose reabsorption resulting in urinary glucose excretion, therebyreducing plasma glucose and HbA1c. The glycemic efficacy of SGLT2inhibitors depends on the amount of glucose filtered through the kidneyand the kidney is potentially a site of ertugliflozin metabolism. Asrenal impairment (RI) is a co-morbidity of T2DM, this study evaluatedthe effect of RI on the pharmacokinetics, pharmacodynamics (as measuredby 24-hour urinary glucose excretion [UGE24]), safety, and tolerabilityof ertugliflozin in subjects with T2DM.

Materials and methods: In this Phase 1, multi-center, open-label study,a single 15 mg oral dose of ertugliflozin was administered in the fastedstate to healthy and T2DM subjects with normal renal function (estimatedglomerular filtration rate [eGFR]≥90 mL/min) and in T2DM subjects withmild RI (eGFR 60-89 mL/min), moderate RI (eGFR 30-59 mL/min) and severeRI (eGFR <30 mL/min). Serial blood samples and urine samples atspecified intervals were collected for 96 hours post-dose forpharmacokinetic evaluation and for measurement of UGE24.

Results: Geometric mean (CV %) values for ertugliflozin exposureparameters (area under the concentration-time curve [AUC_(0-inf)] andpeak concentration [C_(max)]) and change from baseline in UGE24 arepresented in the table below. Ertugliflozin exposures were similar inhealthy subjects and T2DM subjects with normal renal function. Based onan analysis of variance, the geometric mean ratio (GMR) [90% confidenceinterval (CI)] for AUC_(0-inf) in T2DM subjects with mild, moderate, andsevere RI compared to healthy and T2DM subjects with normal renalfunction (pooled) was 1.56 [1.28, 1.91], 1.70 [1.39, 2.08], and 1.55[1.24, 1.94], respectively. The mean GMR [90% CI] for change frombaseline in UGE24 was 0.50 [0.27, 0.91], 0.38 [0.21, 0.70], and 0.14[0.07, 0.27] in T2DM subjects with mild, moderate, and severe RI,respectively, compared to T2DM subjects with normal renal function.

Conclusion: Renal insufficiency moderately increased systemic exposureof ertugliflozin compared to subjects with normal renal function.Despite the higher ertugliflozin exposure, UGE24 decreased withdeclining renal function and a subsequent decrease in the filteredglucose load. A single 15 mg dose of ertugliflozin was well tolerated insubjects with normal renal function and in T2DM subjects with renalimpairment.

Change from baseline in C_(max) AUC_(0-inf) UGE24 Renal Function (ng/mL)(ng · hour/mL) (g) Healthy Normal 219 1236 46.3 (n = 8) (26) (27) (31)T2DM Normal 216 1199 72.3 (n = 6) (35) (42) (30) T2DM Mild RI 313 190836.0 (n = 8) (30) (28) (113)  T2DM Moderate 306 2075 27.6 RI (23) (19)(68) (n = 8) T2DM Severe RI 196 1895 10.1 (n = 6) (28) (23) (57) Note:Values presented are geometric mean (% CV)Protocol for a Phase 3 Study of the Efficacy and Safety of Ertugliflozinin Participants with Type 2 Diabetes Mellitus with Stage 3 ChronicKidney Disease who have Inadequate Glycemic Control on AntihyperglycemicTherapy

This study will evaluate the efficacy and safety of ertugliflozin(MK-8835/PF-04971729) in participants with type 2 diabetes mellitus withStage 3 Chronic Kidney Disease (CKD) who have inadequate glycemiccontrol on background antihyperglycemic therapy. The duration of thistrial will be up to 67 weeks. This will consist of a 1-week ScreeningPeriod, a 10-week wash-off period from metformin, if needed, and a2-week placebo run-in period, a 52-week double-blind treatment period,and a 14-day post-treatment follow-up period. The primary objective ofthis trial is to assess the A1C-lowering efficacy of the addition ofertugliflozin compared to the addition of placebo with an underlyinghypothesis that addition of treatment with ertugliflozin providesgreater reduction in A1C compared to the addition of placebo; theprimary objective will be tested for both 5-mg and 15-mg doses ofertugliflozin.

-   Condition: Type 2 Diabetes Mellitus-   Intervention: Drug: Ertugliflozin; Drug: Placebo-   Phase: Phase 3-   Study Type: Interventional-   Study Design: Allocation: Randomized-   Endpoint Classification: Safety/Efficacy Study-   Intervention Model: Parallel Assignment-   Masking: Double Blind (Subject, Investigator)-   Primary Purpose: Treatment-   Official Title: A Phase III, Multicenter, Randomized, Double-Blind,    Placebo-Controlled Clinical Trial to Evaluate the Efficacy and    Safety of Ertugliflozin (MK-8835/PF-04971729) in Subjects With Type    2 Diabetes Mellitus With Stage 3 Chronic Kidney Disease Who Have    Inadequate Glycemic Control on Background Antihyperglycemic Therapy-   Primary Outcome Measures:    -   Change from Baseline in A1C at Week 26 Overall cohort of Stage 3        CKD, estimated glomerular filtration rate (eGFR) of ≥30 to <60        mL/min/1.73 m²    -   Number of Participants Who Experienced an Adverse Event (AE)    -   Number of Participants Who Discontinued Study Treatment due to        an AE Secondary Outcome Measures:    -   Change from Baseline in A1C at Week 26 Cohort of Stage 3A CKD,        eGFR of ≥45 to <60 mL/min/1.73 m2    -   Change from Baseline in Body Weight at Week 26 Cohort of Stage        3A CKD, eGFR of ≥45 to <60 mL/min/1.73 m2    -   Change from Baseline in Systolic Blood Pressure at Week 26        Cohort of Stage 3A CKD, eGFR of ≥45 to <60 mL/min/1.73 m2    -   Change from Baseline in Fasting Plasma Glucose at Week 26 Cohort        of Stage 3A CKD, eGFR of ≥45 to <60 mL/min/1.73 m2    -   Number of Participants with an A1C of <7% (53 mmol/mol) at Week        26 Cohort of Stage 3A CKD, eGFR of ≥45 to <60 mL/min/1.73 m2-   Arms-   Ertugliflozin, 5 mg, oral, one 5 mg ertugliflozin tablet and one    placebo tablet, once daily for 52 weeks Drug: Ertugliflozin-   Ertugliflozin, 15 mg, oral, one 5 mg and one 10 mg tablet, once    daily for 52 weeks Drug: Ertugliflozin-   Matching placebo Drug: Placebo, oral, tablet, 10 mg or 5 mg and 10    mg tablet once daily for 52 weeks-   Eligibility-   Ages Eligible for Study: 25 Years and older-   Genders Eligible for Study: Both-   Accepts Healthy Volunteers: No-   Inclusion Criteria:    -   Diagnosis of T2DM    -   On stable diabetes therapy (diet/exercise therapy alone or        anti-hyperglycemic agents [AHA] monotherapy or combination        therapy) for at least 6 weeks prior to study participation OR on        metformin (with or without diet/exercise therapy or other AHA        therapy) and is willing to undergo a 10-week metformin wash-off        period    -   Body Mass Index (BMI) greater than or equal to 18.0 kg/m^2    -   Male, postmenopausal female or surgically sterile female    -   If a female of reproductive potential, agrees to remain        abstinent or to use (or have their partner use) 2 acceptable        combinations of birth control while participating in the trial        and for 14 days after the last use of study drug.-   Exclusion Criteria:    -   History of type 1 diabetes mellitus or a history of ketoacidosis    -   History of other specific types of diabetes (e.g., genetic        syndromes, secondary pancreatic diabetes, diabetes due to        endocrine disorders, drug—or chemical-induced, and post-organ        transplant)    -   History of nephrotic range proteinuria with hypoalbuminemia and        edema    -   History of rapidly progressive glomerulonephritis, lupus        nephritis, renal or systemic vasculitis, renal artery stenosis        with renovascular hypertension, or ischemic nephropathy    -   History of familial renal glucosuria    -   History of renal dialysis or renal transplant or renal disease        requiring treatment with any immunosuppressive agent    -   A known hypersensitivity or intolerance to any (sodium-glucose        co-transporter 2) SGLT2 inhibitor    -   On a weight-loss program or weight-loss medication or other        medication associated with weight changes and is not weight        stable    -   Has undergone bariatric surgery within the past 12 months    -   Has been treated with rosiglitazone or other SGLT2 inhibitors        within 12 weeks of study participation    -   Has active, obstructive uropathy or indwelling urinary catheter    -   History of myocardial infarction, unstable angina, arterial        revascularization, stroke, transient ischemic attack, or New        York Heart Association (NYHA) functional class III-IV heart        failure within 3 months of study participation    -   A history of malignancy ≤5 years prior to study participation,        except for adequately treated basal or squamous cell skin cancer        or in situ cervical cancer    -   Known history of Human Immunodeficiency Virus (HIV)    -   Has blood dyscrasias or any disorders causing hemolysis or        unstable red blood cells or any other clinically significant        hematological disorder (such as aplastic anemia,        myeloproliferative or myelodysplastic syndromes,        thrombocytopenia)    -   A medical history of active liver disease (other than        non-alcoholic hepatic steatosis), including chronic active        hepatitis B or C, primary biliary cirrhosis, or active        symptomatic gallbladder disease    -   Has any clinically significant malabsorption condition    -   If taking thyroid replacement therapy, has not been on a stable        dose for at least 6 weeks prior to study participation    -   Has been previously randomized in a study with ertugliflozin    -   Has participated in other studies involving an investigational        drug within 30 days prior or during study participation    -   Has undergone a surgical procedure within 6 weeks prior to or        during study participation    -   Has a positive urine pregnancy test    -   Is pregnant or breast-feeding, or is planning to conceive during        the trial, including 14 days following the last dose of study        medication    -   Planning to undergo hormonal therapy in preparation to donate        eggs during the trial, including 14 days following the last dose        of study medication    -   Excessive consumption of alcoholic beverages or binge drinking    -   Has donated blood or blood products within 6 weeks of study        participation or plans to donate blood or blood products at any        time during the trial

Throughout this application, various publications are referenced. Thedisclosures of these publications in their entireties are herebyincorporated by reference into this application for all purposes.

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the present inventionwithout departing from the scope or spirit of the invention. Otherembodiments of the invention will be apparent to those skilled in theart from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specificationincluding the examples be considered as exemplary only, with a truescope and spirit of the invention being indicated by the followingclaims.

What is claimed is:
 1. A method of treating prediabetes, type 1 or type2 diabetes mellitus in a patient in need thereof comprisingadministering ertugliflozin or a co-crystal or a pharmaceuticallyacceptable salt thereof to the patient, wherein the patient has moderaterenal impairment or stage 3 chronic kidney disease (CKD).
 2. The methodof claim 1, wherein the patient has moderate A renal impairment or stage3A chronic kidney disease (CKD).
 3. The method of claim 1, wherein thepatient has moderate B renal impairment or stage 3B chronic kidneydisease (CKD).
 4. A method for improving glycemic control in a patientwith type 2 diabetes comprising administering ertugliflozin or aco-crystal or a pharmaceutically acceptable salt thereof to the patient,wherein the patient has moderate renal impairment or stage 3 chronickidney disease (CKD).
 5. The method of claim 4, wherein the patient hasmoderate A renal impairment or stage 3A chronic kidney disease (CKD). 6.The method of claim 4, wherein the patient has moderate B renalimpairment or stage 3B chronic kidney disease (CKD).
 7. The method ofclaim 1, wherein ertugliflozin or a co-crystal or a pharmaceuticallyacceptable salt thereof is administered as a pharmaceutical composition.8. The method of claim 1, wherein ertugliflozin or a co-crystal or apharmaceutically acceptable salt thereof is administered in the amountof 5 mg or 15 mg of ertugliflozin.
 9. The method of claim 1, whereinertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof is administered once daily.
 10. The method of claim 1, whereinertugliflozin or a co-crystal or a pharmaceutically acceptable saltthereof is administered with at least one additional pharmaceuticalagent.
 11. The method of claim 10, wherein ertugliflozin or a co-crystalor a pharmaceutically acceptable salt thereof is administered withsitagliptin or a pharmaceutically acceptable salt thereof.
 12. Themethod of claim 11, wherein the sitagliptin or pharmaceuticallyacceptable salt thereof is in the amount of 25 mg or 50 mg.
 13. Themethod of claim 1, wherein the method results in deceased blood pressureand decreased uric acid.